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Li, Qi-Jing

Overview:

To harness the unique immune-potentiating and immune-regulatory properties of T cells, it is of essence to understand and optimize T cell responses. As microRNAs (miRNAs) can serve as effective tools to manipulate a specific immune response, the major objective of my laboratory is to discover new immunoregulatory miRNAs and to employ them to modulate the strength and pattern of T cell responses for clinical intervention, especially, for cancer therapies. Stepping up to the challenges of this interdisciplinary field in its infancy, we have been constructing research programs by developing new technological platforms, fostering collaborations to acquire expertise in various disciplines, and focusing on the translational value of our projects.


Most projects in my laboratory are derived from the robust miRNA profiling platform developed in-house. Through the initial expression profiling, we have been working on key miRNAs as:


(I) non-invasive biomarkers for disease diagnosis and prognosis. Due to their high stability in bodily fluids and sensitivity of detection, miRNAs have the potential to serve as non-invasive disease biomarkers. Working collaboratively with several clinicians, we have identified miRNA signature panels to not only prognose AIDS progression, but also diagnose lung cancer and predict patient responsiveness to chemotherapy.


(II) entities/targets for immunotherapy. By elucidating the roles of specific miRNAs in T cell differentiation, effector function and tumor-immune crosstalk, my laboratory has unveiled multiple miRNA targets for immune-modulation and cancer immunotherapy;


(III) tools for discovery of novel epigenetic regulators that control T cell lineage commitment and plasticity. By studying the interplay between miRNAs and the epigenetic machinery, we have uncovered signaling nodes and protein functions that play previously-unappreciated roles in T cell fate decisions.


Seeking to understand regulatory mechanisms of T cell functions, ongoing work in my laboratory is based on two main foci. The first is to elucidate mechanisms of miRNA turnover during T cell activation. Although miRNAs are dramatically down-regulated upon TCR engagement, the underpinning molecular mechanisms and functional consequences of this dynamic turnover remain poorly-defined. To approach this question, we focused on machineries controlling intracellular vesicle trafficking. Proteomics analysis has helped us identify a new protein-interaction network between the vesicle sorting and miRNA machineries, which may direct intracellular trafficking of miRNAs. The second interest in my laboratory lies in developing miRNA-based immunotherapeutic strategies for cancer intervention. With the clinical relevance and translational value of our research in mind, immunotherapeutic miRNA candidates selected in our studies are first identified from expression profiling of lung cancer patient clinical samples, followed by further validation and characterization in various mouse models of cancer. Having identified several miRNA candidates, our efforts are currently invested in developing the relevant miRNA-targeting gene therapy tools to optimize the persistence and anti-tumor effector functions of both CD4+ and CD8+ T cells in vivo. In collaboration with clinicians at Duke, we are in the process of translating our findings into the clinic, by incorporating our miRNA-targeting moiety into chimeric antigen receptor cell therapy for glioblastoma patients.


Moving forward, while mechanistic aspects of our established research program will continue, new projects my laboratory will take on a more translational approach.  With the support of our basic and clinical research colleagues at Duke, across the county, and in China, we will place greater emphasis on disease states; specifically, how miRNA molecules impact T cell responses during chronic viral infection or in the tumor microenvironment, and how these diseases condition the expression of key miRNAs.

Positions:

Associate Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1996

B.S. — Peking University (China)

Ph.D. 2002

Ph.D. — University of California at Riverside

Research Assistant,

Peking University (China)

Graduate Research,

University of California at Riverside

Grants:

CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
December 01, 2016
End Date
November 30, 2021

Basic Immunology Training Program

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2014
End Date
June 30, 2019

Study of Subglutinol A as a Potential Immunomodulatory Agent

Administered By
Chemistry
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
December 09, 2016
End Date
November 30, 2018

Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 15, 2011
End Date
November 30, 2017

A clinically-relevant anti-CD27 agonist antibody as a vaccine adjuvant for brain tumor immunotherapy

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 2016
End Date
July 31, 2017

microRNA regulates graft-versus-host diseases

Administered By
Immunology
AwardedBy
Medical University of South Carolina
Role
Principal Investigator
Start Date
August 01, 2015
End Date
January 31, 2017
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Publications:

An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage.

Inflammation induced by innate immunity influences the development of T cell-mediated autoimmunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome-independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment. Instead, an alternative inflammatory mechanism, including membrane-bound lymphotoxin-β receptor (LTβR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development, and type B EAE is ameliorated by antagonizing these receptors. Relative expression of Ltbr and Cxcr2 genes was indeed enhanced in patients with IFNβ-resistant multiple sclerosis. Remission was minimal in type B EAE due to neuronal damages induced by semaphorin 6B upregulation on CD4(+) T cells. Our data reveal a new inflammatory mechanism by which an IFNβ-resistant EAE subtype develops.

Authors
Inoue, M; Chen, P-H; Siecinski, S; Li, Q-J; Liu, C; Steinman, L; Gregory, SG; Benner, E; Shinohara, ML
MLA Citation
Inoue, M, Chen, P-H, Siecinski, S, Li, Q-J, Liu, C, Steinman, L, Gregory, SG, Benner, E, and Shinohara, ML. "An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage." Nature neuroscience 19.12 (December 2016): 1599-1609.
PMID
27820602
Source
epmc
Published In
Nature Neuroscience
Volume
19
Issue
12
Publish Date
2016
Start Page
1599
End Page
1609
DOI
10.1038/nn.4421

The MicroRNA miR-191 Supports T Cell Survival Following Common γ Chain Signaling

Authors
Lykken, EA; Li, Q-J
MLA Citation
Lykken, EA, and Li, Q-J. "The MicroRNA miR-191 Supports T Cell Survival Following Common γ Chain Signaling." Journal of Biological Chemistry 291.45 (November 4, 2016): 23532-23544.
Source
crossref
Published In
The Journal of biological chemistry
Volume
291
Issue
45
Publish Date
2016
Start Page
23532
End Page
23544
DOI
10.1074/jbc.M116.741264

Interleukin-2 reverses CD8(+) T cell exhaustion in clinical malignant pleural effusion of lung cancer.

Malignant pleural effusion (MPE) is a poor prognostic sign for cancer patients, whereas the functional condition of MPE CD8(+) T cells is unknown. Intracavitary immunotherapy with interleukin (IL)-2 has been proven effective in controlling MPE. To elucidate the underlying mechanism, 35 lung cancer (LC) patients with MPE and 12 healthy donors were included in this study. For the IL-2 therapy experiments, after draining partial MPE, we treated 14 patients by administrating IL-2 (3 or 5 × 10(6) U in 50 ml saline) into the thoracic cavity. Before and after IL-2 treatment (40-48 h), the MPE and peripheral blood (PB) were obtained from the subjects. PB from healthy volunteers was collected as control. The expression of programmed cell death 1 (PD-1), granzyme B (GzmB), interferon (IFN)-γ and the proliferation were analysed in CD8(+) T cells from MPE and PB. The CD8(+) T cells in the MPE of LC patients showed lowest GzmB, IFN-γ and proliferation but highest PD-1 expression, compared with that in PB of LC patients and healthy donors. IL-2 treatment reduced the expression of PD-1, increased the expression of GzmB and IFN-γ and enhanced the proliferation of CD8(+) T cells in MPE. In addition, IL-2 treatment reduced carcino-embryonic antigen (CEA) level in MPE. These results indicate that MPE CD8(+) T cells exhibit exhaustion phenotype which can be reversed by IL-2 therapy.

Authors
Hu, CY; Zhang, YH; Wang, T; Chen, L; Gong, ZH; Wan, YS; Li, QJ; Li, YS; Zhu, B
MLA Citation
Hu, CY, Zhang, YH, Wang, T, Chen, L, Gong, ZH, Wan, YS, Li, QJ, Li, YS, and Zhu, B. "Interleukin-2 reverses CD8(+) T cell exhaustion in clinical malignant pleural effusion of lung cancer." Clinical and experimental immunology 186.1 (October 2016): 106-114.
PMID
27447482
Source
epmc
Published In
Clinical & Experimental Immunology
Volume
186
Issue
1
Publish Date
2016
Start Page
106
End Page
114
DOI
10.1111/cei.12845

Glimpse of natural selection of long-lived T-cell clones in healthy life.

Homeostatic maintenance of T cells with broad clonal diversity is influenced by both continuing output of young T cells from the thymus and ongoing turnover of preexisting clones in the periphery. In the absence of infection, self and commensal antigens are thought to play important roles in selection and homeostatic maintenance of the T-cell pool. Most naïve T cells are short-lived due to lack of antigen encounter, whereas antigen-experienced T cells may survive and persist as long-lived clones. Thus far, little is known about the homeostasis, antigenic specificity, and clonal diversity of long-lived T-cell clones in peripheral lymphoid organs under healthy living conditions. To identify long-lived T-cell clones in mice, we designed a lineage-tracing method to label a wave of T cells produced in the thymus of young mice. After aging the mice for 1.5 y, we found that lineage-tracked T cells consisted of primarily memory-like T cells and T regulatory cells. T-cell receptor repertoire analysis revealed that the lineage-tracked CD4 memory-like T cells and T regulatory cells exhibited age-dependent enrichment of shared clonotypes. Furthermore, these shared clonotypes were found across different mice maintained in the same housing condition. These findings suggest that nonrandom and shared antigens are involved in controlling selection, retention, and immune tolerance of long-lived T-cell clones under healthy living conditions.

Authors
Zhang, B; Jia, Q; Bock, C; Chen, G; Yu, H; Ni, Q; Wan, Y; Li, Q; Zhuang, Y
MLA Citation
Zhang, B, Jia, Q, Bock, C, Chen, G, Yu, H, Ni, Q, Wan, Y, Li, Q, and Zhuang, Y. "Glimpse of natural selection of long-lived T-cell clones in healthy life." Proceedings of the National Academy of Sciences of the United States of America 113.35 (August 17, 2016): 9858-9863.
PMID
27535935
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
113
Issue
35
Publish Date
2016
Start Page
9858
End Page
9863
DOI
10.1073/pnas.1601634113

Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation.

Signals from the T-cell receptor (TCR) and γ-chain cytokine receptors play crucial roles in initiating activation and effector/memory differentiation of CD8 T-cells. We report here that simultaneous deletion of both diacylglycerol kinase (DGK) α and ζ (DKO) severely impaired expansion of CD8 effector T cells and formation of memory CD8 T-cells after Listeria monocytogenes infection. Moreover, ablation of both DGKα and ζ in preformed memory CD8 T-cells triggered death and impaired homeostatic proliferation of these cells. DKO CD8 T-cells were impaired in priming due to decreased expression of chemokine receptors and migration to the draining lymph nodes. Moreover, DKO CD8 T-cells were unexpectedly defective in NFκB-mediated miR-155 transcript, leading to excessive SOCS1 expression and impaired γ-chain cytokine signaling. Our data identified a DGK-NFκB-miR-155-SOCS1 axis that bridges TCR and γ-chain cytokine signaling for robust CD8 T-cell primary and memory responses to bacterial infection.

Authors
Yang, J; Zhang, P; Krishna, S; Wang, J; Lin, X; Huang, H; Xie, D; Gorentla, B; Huang, R; Gao, J; Li, Q-J; Zhong, X-P
MLA Citation
Yang, J, Zhang, P, Krishna, S, Wang, J, Lin, X, Huang, H, Xie, D, Gorentla, B, Huang, R, Gao, J, Li, Q-J, and Zhong, X-P. "Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation." Oncotarget 7.23 (June 2016): 33744-33764.
PMID
27014906
Source
epmc
Published In
Oncotarget
Volume
7
Issue
23
Publish Date
2016
Start Page
33744
End Page
33764
DOI
10.18632/oncotarget.8164

Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394-405. ©2016 AACR.

Authors
Markowitz, GJ; Yang, P; Fu, J; Michelotti, GA; Chen, R; Sui, J; Yang, B; Qin, W-H; Zhang, Z; Wang, F-S; Diehl, AM; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Markowitz, GJ, Yang, P, Fu, J, Michelotti, GA, Chen, R, Sui, J, Yang, B, Qin, W-H, Zhang, Z, Wang, F-S, Diehl, AM, Li, Q-J, Wang, H, and Wang, X-F. "Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes." Cancer research 76.8 (April 2016): 2394-2405.
PMID
26893476
Source
epmc
Published In
Cancer Research
Volume
76
Issue
8
Publish Date
2016
Start Page
2394
End Page
2405
DOI
10.1158/0008-5472.can-15-1548

MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease.

Authors
Xu, X; Zhang, Y; Jasper, J; Lykken, E; Alexander, PB; Markowitz, GJ; McDonnell, DP; Li, Q-J; Wang, X-F
MLA Citation
Xu, X, Zhang, Y, Jasper, J, Lykken, E, Alexander, PB, Markowitz, GJ, McDonnell, DP, Li, Q-J, and Wang, X-F. "MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer." Oncotarget 7.15 (April 2016): 20381-20394.
PMID
26967387
Source
epmc
Published In
Oncotarget
Volume
7
Issue
15
Publish Date
2016
Start Page
20381
End Page
20394
DOI
10.18632/oncotarget.7953

MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium.

Upon antigen engagement, augmented cytosolic reactive oxygen species (ROS) are needed to achieve optimal T cell receptor (TCR) signaling. However, uncontrolled ROS production is a prominent cause of necrosis, which elicits hyper-inflammation and tissue damage. Hence, it is critical to program activated T cells to achieve ROS equilibrium. Here, we determined that miR-23a is indispensable for effector CD4(+) T cell expansion, particularly by providing early protection from excessive necrosis. Mechanistically, miR-23a targeted PPIF, gatekeeper of the mitochondria permeability transition pore, thereby restricting ROS flux and maintaining mitochondrial integrity. Upon acute Listeria monocytogenes infection, deleting miR-23a in T cells resulted in excessive inflammation, massive liver damage, and a marked mortality increase, which highlights the essential role of miR-23a in maintaining immune homeostasis.

Authors
Zhang, B; Liu, S-Q; Li, C; Lykken, E; Jiang, S; Wong, E; Gong, Z; Tao, Z; Zhu, B; Wan, Y; Li, Q-J
MLA Citation
Zhang, B, Liu, S-Q, Li, C, Lykken, E, Jiang, S, Wong, E, Gong, Z, Tao, Z, Zhu, B, Wan, Y, and Li, Q-J. "MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium." Immunity 44.3 (March 2016): 568-581.
PMID
26921109
Source
epmc
Published In
Immunity
Volume
44
Issue
3
Publish Date
2016
Start Page
568
End Page
581
DOI
10.1016/j.immuni.2016.01.007

Analysis of the Rab GTPase Interactome in Dendritic Cells Reveals Anti-microbial Functions of the Rab32 Complex in Bacterial Containment.

Dendritic cells (DCs) orchestrate complex membrane trafficking through an interconnected transportation network linked together by Rab GTPases. Through a tandem affinity purification strategy and mass spectrometry, we depicted an interactomic landscape of major members of the mammalian Rab GTPase family. When complemented with imaging tools, this proteomic analysis provided a global view of intracellular membrane organization. Driven by this analysis, we investigated dynamic changes to the Rab32 subnetwork in DCs induced by L. monocytogenes infection and uncovered an essential role of this subnetwork in controlling the intracellular proliferation of L. monocytogenes. Mechanistically, Rab32 formed a persistent complex with two interacting proteins, PHB and PHB2, to encompass bacteria both during early phagosome formation and after L. monocytogenes escaped the original containment vacuole. Collectively, we have provided a functional compartmentalization overview and an organizational framework of intracellular Rab-mediated vesicle trafficking that can serve as a resource for future investigations.

Authors
Li, Y; Wang, Y; Zou, L; Tang, X; Yang, Y; Ma, L; Jia, Q; Ni, Q; Liu, S; Tang, L; Lin, R; Wong, E; Sun, W; Wang, L; Wei, Q; Ran, H; Zhang, L; Lian, H; Huang, W; Wu, Y; Li, Q-J; Wan, Y
MLA Citation
Li, Y, Wang, Y, Zou, L, Tang, X, Yang, Y, Ma, L, Jia, Q, Ni, Q, Liu, S, Tang, L, Lin, R, Wong, E, Sun, W, Wang, L, Wei, Q, Ran, H, Zhang, L, Lian, H, Huang, W, Wu, Y, Li, Q-J, and Wan, Y. "Analysis of the Rab GTPase Interactome in Dendritic Cells Reveals Anti-microbial Functions of the Rab32 Complex in Bacterial Containment." Immunity 44.2 (February 2016): 422-437.
PMID
26885862
Source
epmc
Published In
Immunity
Volume
44
Issue
2
Publish Date
2016
Start Page
422
End Page
437
DOI
10.1016/j.immuni.2016.01.027

MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Authors
Hu, J; Sun, T; Wang, H; Chen, Z; Wang, S; Yuan, L; Liu, T; Li, H-R; Wang, P; Feng, Y; Wang, Q; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Rathmell, J; Fu, X-D; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Hu, J, Sun, T, Wang, H, Chen, Z, Wang, S, Yuan, L, Liu, T, Li, H-R, Wang, P, Feng, Y, Wang, Q, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Rathmell, J, Fu, X-D, Li, Q-J, Wang, H, and Wang, X-F. "MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B." Cancer cell 29.1 (January 2016): 49-60.
Website
http://hdl.handle.net/10161/11667
PMID
26766590
Source
epmc
Published In
Cancer Cell
Volume
29
Issue
1
Publish Date
2016
Start Page
49
End Page
60
DOI
10.1016/j.ccell.2015.12.005

The tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis.

One of the most important factors that limit the potency of CD8+ cytotoxic T lymphocyte (CTL) responses is the tumor microenvironment (TME). Here, we provide evidence that miR-26a is a negative regulator of CTL function in the TME. Specifically, we identified miR-26a as a crucial suppressor gene in CTLs from the TME, as we found that, miR-26a expression was elevated in CTLs to respond to TME secretome stimulation. CTLs from miR-26a-transgenic mice showed impaired IFNγ and granzyme B production in response to their cognate antigen. Conversely, we found that miR-26a inhibition in CTLs could effectively increase the cytotoxicity and suppress tumor growth. Mechanically, we identified EZH2 as a direct target of miR-26a. miR-26a and EZH2 expression were found to be inversely correlated in CTLs, and the inhibition of EZH2 in CTLs impairs CTL function. These functional correlations were validated in a cohort of non-small cell lung cancer patients, indicating that the miR-26a-EZH2 axis is clinically relevant. Our findings suggested that miR-26a silencing as a novel strategy to improve the efficacy of CTL-based cancer immunotherapy.

Authors
Long, H; Xiang, T; Luo, J; Li, F; Lin, R; Liu, S; Jiang, S; Hu, C; Chen, G; Wong, E; Wan, Y; Li, Q-J; Zhu, B
MLA Citation
Long, H, Xiang, T, Luo, J, Li, F, Lin, R, Liu, S, Jiang, S, Hu, C, Chen, G, Wong, E, Wan, Y, Li, Q-J, and Zhu, B. "The tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis." Oncoimmunology 5.12 (January 2016): e1245267-.
PMID
28123882
Source
epmc
Published In
OncoImmunology
Volume
5
Issue
12
Publish Date
2016
Start Page
e1245267
DOI
10.1080/2162402x.2016.1245267

Targeting the Wnt-Regulatory Protein CTNNBIP1 by microRNA-214 Enhances the Stemness and Self-Renewal of Cancer Stem-Like Cells in Lung Adenocarcinomas.

A novel hypothesis in cancer biology proposes that cancer growth is driven by cancer stem-like cells (CSLCs), also called tumor-initiating cells, which can self-renew and differentiate into multilineage progeny in a fashion similar to stem cells. However, the impact and underlying mechanisms of this process in lung adenocarcinoma (LAC) remain to be elucidated. Here, we report that microRNA-214 (miR-214) contributes to cell self-renewal by directly targeting catenin beta interacting protein 1 (CTNNBIP1), a member of the Wnt signaling pathway. We demonstrate that miR-214 overexpression enhances stem-like properties in LAC cells and that miR-214 shows increased expression in CSLCs derived from primary tumor tissue and from two LAC cell lines (A549 and NCI-H1650). Strikingly, downregulation of miR-214 expression in CSLCs resulted in a significant decrease in spheroid formation and the expression of the stem-cell markers Nanog, Oct-4, and Sox-2. Finally, CTNNBIP1 was identified as a target of miR-214. miR-214 expression in LAC was negatively correlated with CTNNBIP1 expression and positively correlated with differentiated cellular states. Moreover, CTNNBIP1 expression correlated with longer overall survival in LAC patients. This study reveals that miR-214 plays a critical role in CSLC self-renewal and stemness by targeting CTNNBIP1. The identification of this functional miR-214-CTNNBIP1 interaction that regulates self-renewal in CSLCs has the potential to direct the development of novel therapeutic strategies for LAC.

Authors
Qi, W; Chen, J; Cheng, X; Huang, J; Xiang, T; Li, Q; Long, H; Zhu, B
MLA Citation
Qi, W, Chen, J, Cheng, X, Huang, J, Xiang, T, Li, Q, Long, H, and Zhu, B. "Targeting the Wnt-Regulatory Protein CTNNBIP1 by microRNA-214 Enhances the Stemness and Self-Renewal of Cancer Stem-Like Cells in Lung Adenocarcinomas." Stem cells (Dayton, Ohio) 33.12 (December 2015): 3423-3436.
PMID
26299367
Source
epmc
Published In
Stem Cells
Volume
33
Issue
12
Publish Date
2015
Start Page
3423
End Page
3436
DOI
10.1002/stem.2188

microRNA-214 promotes epithelial-mesenchymal transition and metastasis in lung adenocarcinoma by targeting the suppressor-of-fused protein (Sufu).

Distant metastasis is the major cause of cancer-related deaths in patients with lung adenocarcinoma (LAD). Emerging evidence reveals that miRNA is critical for tumor metastasis. miR-214 expression has been associated with LAD progression. However, whether and how miR-214 is involved in the development and metastasis of LAD remain unaddressed. Here, we found that the expression of miR-214 was elevated in LAD and correlated positively with LAD metastasis and epithelial-mesenchymal transition (EMT). In addition, we found that miR-214 enhanced the molecular program controlling the EMT of LAD cells and promoted LAD cell metastasis both in vitro and in vivo. This study thus provides the first evidence to show that the miR-214 expression by LAD cells contributes to the EMT and metastasis of LAD. Mechanistically, Sufu was identified as an important miR-214 functional target for the EMT and metastasis of LAD, ectopic expression of Sufu alleviated miR-214 promoted EMT and metastasis. Importantly, the expression of Sufu inversely correlated with the expression of miR-214 and vimentin and positively associated with the expression of E-cadherin in the tumor cells from human LAD patients. Collectively, this study uncovers a previously unappreciated miR-214-Sufu pathway in controlling EMT and metastasis of LAD and suggests that interfering with miR-214 and Sufu could be a viable approach to treat late stage metastatic LAD patients.

Authors
Long, H; Wang, Z; Chen, J; Xiang, T; Li, Q; Diao, X; Zhu, B
MLA Citation
Long, H, Wang, Z, Chen, J, Xiang, T, Li, Q, Diao, X, and Zhu, B. "microRNA-214 promotes epithelial-mesenchymal transition and metastasis in lung adenocarcinoma by targeting the suppressor-of-fused protein (Sufu)." Oncotarget 6.36 (November 2015): 38705-38718.
PMID
26462018
Source
epmc
Published In
Oncotarget
Volume
6
Issue
36
Publish Date
2015
Start Page
38705
End Page
38718
DOI
10.18632/oncotarget.5478

MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice.

MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.

Authors
Wu, Y; Heinrichs, J; Bastian, D; Fu, J; Nguyen, H; Schutt, S; Liu, Y; Jin, J; Liu, C; Li, Q-J; Xia, C; Yu, X-Z
MLA Citation
Wu, Y, Heinrichs, J, Bastian, D, Fu, J, Nguyen, H, Schutt, S, Liu, Y, Jin, J, Liu, C, Li, Q-J, Xia, C, and Yu, X-Z. "MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice." Blood 126.11 (September 2015): 1314-1323.
PMID
26138686
Source
epmc
Published In
Blood
Volume
126
Issue
11
Publish Date
2015
Start Page
1314
End Page
1323
DOI
10.1182/blood-2015-02-627356

Regulation of T cell function by microRNA-720.

Chronic hepatitis B virus (HBV) infection is a major global health burden. Functional exhaustion and numerical reduction of HBV-specific cytotoxic T lymphocytes (CTLs) in the liver and peripheral blood limit anti-HBV CTL activity in patients with chronic HBV infection (CHB). However, the ongoing anti-HBV CD8(+) T cell responses in the lymphoid organs are largely unknown due to the infeasibility of obtaining lymphoid organs from CHB patients. Here we demonstrate that the percentage of HBV-specific CD8(+) T cells is higher in the spleen of CHB patients than that from peripheral blood and liver. Although they do respond to TCR stimulation and produce IFNγ, the cells proliferate poorly. Furthermore, miR-720 expression is upregulated in HBV-specific CD8(+) T cells. Overexpression of miR-720 in primary human CD8(+) T cells inhibits TCR stimulation-induced proliferation. We also demonstrate that TGFβ sustains miR-720 upregulation after TCR stimulation, and blood TGFβ levels are associated with the outcome of type I interferon treatment of CHB patients. Thus, therapies targeting miR-720 may help restore impaired immunity in CHB patients.

Authors
Wang, Y; Zhang, Z; Ji, D; Chen, G-F; Feng, X; Gong, L-L; Guo, J; Li, Z-W; Chen, C-F; Zhao, B-B; Li, Z-G; Li, Q-J; Yan, H-P; Sempowski, G; Wang, F-S; He, Y-W
MLA Citation
Wang, Y, Zhang, Z, Ji, D, Chen, G-F, Feng, X, Gong, L-L, Guo, J, Li, Z-W, Chen, C-F, Zhao, B-B, Li, Z-G, Li, Q-J, Yan, H-P, Sempowski, G, Wang, F-S, and He, Y-W. "Regulation of T cell function by microRNA-720." Scientific reports 5 (July 22, 2015): 12159-.
PMID
26199080
Source
epmc
Published In
Scientific Reports
Volume
5
Publish Date
2015
Start Page
12159
DOI
10.1038/srep12159

Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer

Authors
Jia, Q; Zhou, J; Chen, G; Shi, Y; Yu, H; Guan, P; Lin, R; Jiang, N; Yu, P; Li, Q-J; Wan, Y
MLA Citation
Jia, Q, Zhou, J, Chen, G, Shi, Y, Yu, H, Guan, P, Lin, R, Jiang, N, Yu, P, Li, Q-J, and Wan, Y. "Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer." OncoImmunology 4.4 (April 3, 2015): e1001230-e1001230.
Website
http://hdl.handle.net/10161/11568
Source
crossref
Published In
OncoImmunology
Volume
4
Issue
4
Publish Date
2015
Start Page
e1001230
End Page
e1001230
DOI
10.1080/2162402X.2014.1001230

miR-23a blockade enhances adoptive T cell transfer therapy by preserving immune-competence in the tumor microenvironment.

In adoptive T cell transfer therapy (ACT), the antitumor efficacy of cytotoxic CD8(+) T lymphocytes (CTLs) has been limited by tumor-induced immunosuppression. We have demonstrated that miR-23a blockade in tumor-specific CTLs conferred resilience to TGFβ-mediated immunosuppression, resulting in superior tumor control. Our studies highlight miR-23a in tumor-specific CTLs as a clinically relevant target to enhance ACT.

Authors
Lin, R; Sampson, JH; Li, Q-J; Zhu, B
MLA Citation
Lin, R, Sampson, JH, Li, Q-J, and Zhu, B. "miR-23a blockade enhances adoptive T cell transfer therapy by preserving immune-competence in the tumor microenvironment." Oncoimmunology 4.3 (March 2015): e990803-.
PMID
25949909
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
Start Page
e990803
DOI
10.4161/2162402x.2014.990803

Association of CD8(+) T lymphocyte repertoire spreading with the severity of DRESS syndrome.

T-cell receptor (TCR)-mediated cross-recognition is a major mechanism in the pathogenesis of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. However, the characteristics of the TCR repertoire and the clinical significance of repertoire reformation throughout the course of DRESS are unknown. Here, we isolated CD4(+) and CD8(+) T-cells from peripheral blood of 8 DRESS patients at 10-day intervals and, sequenced CDR3-regions of the TCRB chain by high-throughput sequencing to analyze the dynamic reformation in the T-cell repertoire hierarchy. Compared with healthy donors, T-cell expanded in peripheral repertoires from DRESS patient. The extent of fluctuation of dominant CD8(+) T-cell clones, but not of CD4(+) counterparts, correlated positively with the clinical severity and helped classify the enrolled subjects into "fluctuant" and "flat" repertoire groups. The anti-herpesvirus response, which was measured using anti-EBV/HHV antibodies, and the proportion of the homologous CD8(+) EBV-specific clonotypes, in the "fluctuant" group was substantial higher than that in the "flat" group. Furthermore, autoimmune sequelae were observed in a cured "fluctuant" patient. Collectively, the clinical relevance of the fluctuant CD8(+) T-cell repertoires supports the notion that herpes virus-mediated continuously de novo priming of newly pathogenic CD8(+) T-cell clones is an alternate mechanism responsible for the pathogenicity of DRESS.

Authors
Niu, J; Jia, Q; Ni, Q; Yang, Y; Chen, G; Yang, X; Zhai, Z; Yu, H; Guan, P; Lin, R; Song, Z; Li, Q-J; Hao, F; Zhong, H; Wan, Y
MLA Citation
Niu, J, Jia, Q, Ni, Q, Yang, Y, Chen, G, Yang, X, Zhai, Z, Yu, H, Guan, P, Lin, R, Song, Z, Li, Q-J, Hao, F, Zhong, H, and Wan, Y. "Association of CD8(+) T lymphocyte repertoire spreading with the severity of DRESS syndrome." Scientific reports 5 (January 2015): 9913-.
PMID
25905582
Source
epmc
Published In
Scientific Reports
Volume
5
Publish Date
2015
Start Page
9913
DOI
10.1038/srep09913

MicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3.

Peripherally derived regulatory T (pT(reg)) cell generation requires T-cell receptor (TCR) signalling and the cytokines TGF-β1 and IL-2. Here we show that TCR signalling induces the microRNA miR-31, which negatively regulates pT(reg)-cell generation. miR-31 conditional deletion results in enhanced induction of pT(reg) cells, and decreased severity of experimental autoimmune encephalomyelitis (EAE). Unexpectedly, we identify Gprc5a as a direct target of miR-31. Gprc5a is known as retinoic acid-inducible protein 3, and its deficiency leads to impaired pT(reg-)cell induction and increased EAE severity. By generating miR-31 and Gprc5a double knockout mice, we show that miR-31 promotes the development of EAE through inhibiting Gprc5a. Thus, our data identify miR-31 and its target Gprc5a as critical regulators for pT(reg)-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional T(reg) cells in autoimmune diseases.

Authors
Zhang, L; Ke, F; Liu, Z; Bai, J; Liu, J; Yan, S; Xu, Z; Lou, F; Wang, H; Zhu, H; Sun, Y; Cai, W; Gao, Y; Li, Q; Yu, X-Z; Qian, Y; Hua, Z; Deng, J; Li, Q-J; Wang, H
MLA Citation
Zhang, L, Ke, F, Liu, Z, Bai, J, Liu, J, Yan, S, Xu, Z, Lou, F, Wang, H, Zhu, H, Sun, Y, Cai, W, Gao, Y, Li, Q, Yu, X-Z, Qian, Y, Hua, Z, Deng, J, Li, Q-J, and Wang, H. "MicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3." Nature communications 6 (January 2015): 7639-.
PMID
26165721
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
7639
DOI
10.1038/ncomms8639

Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression.

CD8(+) cytotoxic T lymphocytes (CTLs) have potent antitumor activity and therefore are leading candidates for use in tumor immunotherapy. The application of CTLs for clinical use has been limited by the susceptibility of ex vivo-expanded CTLs to become dysfunctional in response to immunosuppressive microenvironments. Here, we developed a microRNA-targeting (miRNA-targeting) approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor BLIMP-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CTLs, and expression correlated with impaired antitumor potential of patient CTLs. We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CTLs that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF-β-mediated tumor immune-evasion pathway.

Authors
Lin, R; Chen, L; Chen, G; Hu, C; Jiang, S; Sevilla, J; Wan, Y; Sampson, JH; Zhu, B; Li, Q-J
MLA Citation
Lin, R, Chen, L, Chen, G, Hu, C, Jiang, S, Sevilla, J, Wan, Y, Sampson, JH, Zhu, B, and Li, Q-J. "Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression." The Journal of clinical investigation 124.12 (December 2014): 5352-5367.
PMID
25347474
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
12
Publish Date
2014
Start Page
5352
End Page
5367
DOI
10.1172/jci76561

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways.

Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.

Authors
Wang, H; Sun, T; Hu, J; Zhang, R; Rao, Y; Wang, S; Chen, R; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Wang, H, Sun, T, Hu, J, Zhang, R, Rao, Y, Wang, S, Chen, R, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Li, Q-J, Wang, H, and Wang, X-F. "miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways." The Journal of clinical investigation 124.10 (October 2014): 4489-4502.
PMID
25202981
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
10
Publish Date
2014
Start Page
4489
End Page
4502
DOI
10.1172/jci75284

MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation.

Forkhead box P3(+) (Foxp3(+)) regulatory T cells (Tregs) are crucial for peripheral tolerance. During inflammation, steady Foxp3 expression in Tregs is essential for maintaining their lineage identity and suppressive function. However, the molecular machinery governing Tregs' resilience to inflammation-induced Foxp3 destabilization remains elusive. Here, we demonstrate that methyl-CpG binding protein 2 (MeCP2), an eminent epigenetic regulator known primarily as the etiological factor of Rett syndrome, is critical to sustain Foxp3 expression in Tregs during inflammation. In response to inflammatory stimuli, MeCP2 is specifically recruited to the Conserved Non-Coding sequence 2 region of the foxp3 locus, where it collaborates with cAMP responsive element binding protein 1 to promote local histone H3 acetylation, thereby counteracting inflammation-induced epigenetic silencing of foxp3. Consequently, Treg-specific deletion of MeCP2 causes spontaneous immune activation in mice and failure in protection against autoimmunity. Furthermore, we demonstrate that Foxp3 expression in MeCP2-deficient Tregs diminishes with time, resulting in their failure to suppress effector T-cell-mediated colitis. Thus, MeCP2 serves as a critical safeguard that confers Tregs with resilience against inflammation.

Authors
Li, C; Jiang, S; Liu, S-Q; Lykken, E; Zhao, L-T; Sevilla, J; Zhu, B; Li, Q-J
MLA Citation
Li, C, Jiang, S, Liu, S-Q, Lykken, E, Zhao, L-T, Sevilla, J, Zhu, B, and Li, Q-J. "MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation." Proceedings of the National Academy of Sciences of the United States of America 111.27 (July 2014): E2807-E2816.
PMID
24958888
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
27
Publish Date
2014
Start Page
E2807
End Page
E2816
DOI
10.1073/pnas.1401505111

miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation.

The miR-17-92 cluster regulates a broad spectrum of biological processes of T cell immunity. This cluster was found to facilitate T cell proliferation, enhance antitumor activities and promote T cell-dependent antibody responses. However, little is known about the role of this miRNA cluster in the development of autoimmune diseases. Multiple sclerosis is a neuro-destructive autoimmune disease caused by the pathogenicity of TH17 cells, whose differentiation is tightly controlled by a variety of transcriptional and post-transcriptional regulators. Our study unveils the critical role of miR-17-92 in TH17 differentiation: T cell-specific miR-17-92 deficiency reduced TH17 differentiation and ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. We demonstrated that miR-17 and miR-19b are the two miRNAs in this cluster responsible for promoting TH17 responses. MiR-19b represses the expression of Phosphatase and Tensin Homology (PTEN), thereby augmenting the PI3K-AKT-mTOR axis essential for proper TH17 differentiation. Meanwhile, miR-17 enhances TH17 polarization by inhibiting a novel target, Ikaros Family Zinc Finger 4 (IKZF4). By establishing the miR-17-92 cluster as a key driver of TH17 responses, our data identify this miRNA cluster as a potential therapeutic target for the clinical intervention of multiple sclerosis.

Authors
Liu, S-Q; Jiang, S; Li, C; Zhang, B; Li, Q-J
MLA Citation
Liu, S-Q, Jiang, S, Li, C, Zhang, B, and Li, Q-J. "miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation." The Journal of biological chemistry 289.18 (May 2014): 12446-12456.
PMID
24644282
Source
epmc
Published In
The Journal of biological chemistry
Volume
289
Issue
18
Publish Date
2014
Start Page
12446
End Page
12456
DOI
10.1074/jbc.m114.550723

Biological evaluation of subglutinol a as a novel immunosuppressive agent for inflammation intervention.

Subglutinol A (1) is an immunosuppressive natural product isolated from Fusarium subglutinans, an endophytic fungus from the vine Tripterygium wilfordii. We show that 1 exerts multimodal immune-suppressive effects on activated T cells in vitro: subglutinol A (1) effectively blocks T cell proliferation and survival while profoundly inhibiting pro-inflammatory IFNγ and IL-17 production by fully differentiated effector Th1 and Th17 cells. Our data further reveal that 1 may exert its anti-inflammatory effects by exacerbating mitochondrial damage in T cells. Additionally, we demonstrate that 1 significantly reduces lymphocytic infiltration into the footpad and ameliorates footpad swelling in the mouse model of Th1-driven delayed-type hypersensitivity. These results suggest the potential of 1 as a novel therapeutic for inflammatory diseases.

Authors
Lin, R; Kim, H; Hong, J; Li, Q-J
MLA Citation
Lin, R, Kim, H, Hong, J, and Li, Q-J. "Biological evaluation of subglutinol a as a novel immunosuppressive agent for inflammation intervention." ACS medicinal chemistry letters 5.5 (May 2014): 485-490.
PMID
24900866
Source
epmc
Published In
ACS Medicinal Chemistry Letters
Volume
5
Issue
5
Publish Date
2014
Start Page
485
End Page
490
DOI
10.1021/ml4004809

MeCP2 reinforces STAT3 signaling and the generation of effector CD4+ T cells by promoting miR-124-mediated suppression of SOCS5.

Methyl CpG binding protein 2 (MeCP2) is an X-linked, multifunctional epigenetic regulator that is best known for its role in the neurological disorder Rett syndrome; however, it is also linked to multiple autoimmune disorders. We examined a potential role for MeCP2 in regulating the responses of CD4+ T cells to stimulation with antigen. MeCP2 was indispensable for the differentiation of naïve CD4+ T cells into T helper type 1 (T(H)1) and T(H)17 cells and for T(H)1- or T(H)17-mediated pathologies in vitro and in vivo. Loss of MeCP2 in CD4+ T cells impaired the expression of the microRNA (miR) miR-124 and consequently relieved miR-124-mediated repression of the translation of suppressor of cytokine signaling 5 (Socs5) mRNA. The resulting accumulation of SOCS5 inhibited the cytokine-dependent activation of signal transducer and activator of transcription 1 (STAT1) and STAT3, which are necessary for the differentiation of T(H)1 and T(H)17 cells, respectively. Upon silencing of MeCP2, primary neurons and astrocytes also failed to respond properly to STAT3-dependent signaling stimulated by neurotrophic factors. Together, these findings suggest that the regulation of STAT3 signaling may represent a common etiology underpinning the roles of MeCP2 in both the nervous and immune systems.

Authors
Jiang, S; Li, C; McRae, G; Lykken, E; Sevilla, J; Liu, S-Q; Wan, Y; Li, Q-J
MLA Citation
Jiang, S, Li, C, McRae, G, Lykken, E, Sevilla, J, Liu, S-Q, Wan, Y, and Li, Q-J. "MeCP2 reinforces STAT3 signaling and the generation of effector CD4+ T cells by promoting miR-124-mediated suppression of SOCS5." Science signaling 7.316 (March 11, 2014): ra25-.
PMID
24619648
Source
epmc
Published In
Science Signaling
Volume
7
Issue
316
Publish Date
2014
Start Page
ra25
DOI
10.1126/scisignal.2004824

A Single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4+ T Cells

We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4+ Tcell functional sensitivity. We found that naive Tcells, Tcell blasts, and memory Tcells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ~1,000, ~10,000, and ~10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting Tcell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4+ Tcell cytokine responses involves increasingly efficient Tcell recruitment rather than greater cytokine production per cell. © 2013 Elsevier Inc.

Authors
Huang, J; Brameshuber, M; Zeng, X; Xie, J; Li, QJ; Chien, YH; Valitutti, S; Davis, MM
MLA Citation
Huang, J, Brameshuber, M, Zeng, X, Xie, J, Li, QJ, Chien, YH, Valitutti, S, and Davis, MM. "A Single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4+ T Cells." Immunity 39.5 (November 14, 2013): 846-857.
PMID
24120362
Source
scopus
Published In
Immunity
Volume
39
Issue
5
Publish Date
2013
Start Page
846
End Page
857
DOI
10.1016/j.immuni.2013.08.036

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) were significantly upregulated in the plasma of aGVHD patients (n = 116) when compared with non-GVHD patients (n = 52) in training and validation phases. We have developed a model including 4 miRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) that can predict the probability of aGVHD with an area under the curve of 0.80. Moreover, these elevated miRNAs were detected before the onset of aGVHD (median = 16 days before diagnosis). In addition, the levels of these miRNAs were positively associated with aGVHD severity, and high expression of the miRNA panel was associated with poor overall survival. Furthermore, the miRNA signature for aGVHD was not detected in the plasma of lung transplant or nontransplant sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as an independent biomarker for the prediction, diagnosis, and prognosis of aGVHD.

Authors
Xiao, B; Wang, Y; Li, W; Baker, M; Guo, J; Corbet, K; Tsalik, EL; Li, Q-J; Palmer, SM; Woods, CW; Li, Z; Chao, NJ; He, Y-W
MLA Citation
Xiao, B, Wang, Y, Li, W, Baker, M, Guo, J, Corbet, K, Tsalik, EL, Li, Q-J, Palmer, SM, Woods, CW, Li, Z, Chao, NJ, and He, Y-W. "Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease." Blood 122.19 (November 7, 2013): 3365-3375.
PMID
24041574
Source
pubmed
Published In
Blood
Volume
122
Issue
19
Publish Date
2013
Start Page
3365
End Page
3375
DOI
10.1182/blood-2013-06-510586

Tracking proliferative history in lymphocyte development with cre-mediated sister chromatid recombination.

Tracking and isolating live cells based on their proliferative history in live animals remains a technical challenge in animal studies. We have designed a genetic marking system for tracking the proliferative frequency and history of lymphocytes during their development and homeostatic maintenance. This system is based on activation of a fluorescent marker after Cre-dependent recombination between sister chromatids at a specially designed tandem loxP site, named Tlox. We have demonstrated the utility of the Tlox system in tracking proliferative windows of B and T lymphocyte development. We have further applied the Tlox system in the analysis of the proliferative behavior and homeostatic maintenance of Vγ1.1 positive γδ T cells. Our data show that Vγ1.1 T cells generated in neonatal but not adult life are able to expand in the thymus. The expanded Vγ1.1 T cells are preferentially maintained in the liver but not in lymphoid organs. It has been shown that numbers of Vγ1.1 T cells were dramatically increased in the lymphoid organs of Id3 deficient mice. By combining BrdU and Tlox assays we show that this phenotype is primarily due to enhanced neonatal expansion and subsequent retention of Vγ1.1 T cells. Thus, the Tlox system provides a new genetic tool to track clonal expansion within a defined cell population or tissue type in live animals.

Authors
Zhang, B; Dai, M; Li, Q-J; Zhuang, Y
MLA Citation
Zhang, B, Dai, M, Li, Q-J, and Zhuang, Y. "Tracking proliferative history in lymphocyte development with cre-mediated sister chromatid recombination." PLoS Genet 9.10 (October 2013): e1003887-.
PMID
24204301
Source
pubmed
Published In
PLoS genetics
Volume
9
Issue
10
Publish Date
2013
Start Page
e1003887
DOI
10.1371/journal.pgen.1003887

T cell receptor (TCR) and transforming growth factor β (TGF-β) signaling converge on DNA (cytosine-5)-methyltransferase to control forkhead box protein 3 (foxp3) locus methylation and inducible regulatory T cell differentiation.

Naïve T cells can be induced to differentiate into Foxp3(+) regulatory T cells (iTregs) upon suboptimal T cell receptor (TCR) stimulus or TCR stimulus in conjunction with TGF-β signaling; however, we do not fully understand how these signals coordinately control foxp3 expression. Here, we show that strong TCR activation, in terms of both duration and ligand affinity, causes the accumulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and DNMT3b and their specific enrichment at the foxp3 locus, which leads to increased CpG methylation and inhibits foxp3 transcription. During this process the augmentation of DNMT1 is regulated through at least two post-transcriptional mechanisms; that is, strong TCR signal inactivates GSK3β to rescue DNMT1 protein from proteasomal degradation, and strong TCR signal suppresses miR-148a to derepress DNMT1 mRNA translation. Meanwhile, TGF-β signaling antagonizes DNMT1 accumulation via activation of p38 MAP kinase. Thus, independent of transcription factor activation, TCR and TGF-β signals converge on DNMT1 to modulate the expression of foxp3 epigenetically, which marks mother cell iTreg lineage choice within the genome of differentiating daughter cells.

Authors
Li, C; Ebert, PJR; Li, Q-J
MLA Citation
Li, C, Ebert, PJR, and Li, Q-J. "T cell receptor (TCR) and transforming growth factor β (TGF-β) signaling converge on DNA (cytosine-5)-methyltransferase to control forkhead box protein 3 (foxp3) locus methylation and inducible regulatory T cell differentiation." J Biol Chem 288.26 (June 28, 2013): 19127-19139.
PMID
23687305
Source
pubmed
Published In
The Journal of biological chemistry
Volume
288
Issue
26
Publish Date
2013
Start Page
19127
End Page
19139
DOI
10.1074/jbc.M113.453357

miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis.

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126(*), a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126(*) directly inhibit stromal cell-derived factor-1 alpha (SDF-1α) expression, and indirectly suppress the expression of chemokine (C-C motif) ligand 2 (Ccl2) by cancer cells in an SDF-1α-dependent manner. miR-126/miR-126(*) expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126(*) downregulation and poor metastasis-free survival of breast cancer patients.

Authors
Zhang, Y; Yang, P; Sun, T; Li, D; Xu, X; Rui, Y; Li, C; Chong, M; Ibrahim, T; Mercatali, L; Amadori, D; Lu, X; Xie, D; Li, Q-J; Wang, X-F
MLA Citation
Zhang, Y, Yang, P, Sun, T, Li, D, Xu, X, Rui, Y, Li, C, Chong, M, Ibrahim, T, Mercatali, L, Amadori, D, Lu, X, Xie, D, Li, Q-J, and Wang, X-F. "miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis." Nat Cell Biol 15.3 (March 2013): 284-294.
PMID
23396050
Source
pubmed
Published In
Nature Cell Biology
Volume
15
Issue
3
Publish Date
2013
Start Page
284
End Page
294
DOI
10.1038/ncb2690

mir-17-92: A polycistronic oncomir with pleiotropic functions

Neoplastic transformation is caused by accumulation of genetic lesions that ultimately convert normal cells into tumor cells with uncontrolled proliferation and survival, unlimited replicative potential, and invasive growth. Emerging evidence has highlighted the functional importance of non-coding RNAs, particularly microRNAs (miRNAs), in the initiation and progression of tumor development. The mir-17-92 miRNA is among the best characterized miRNA oncogenes, whose genomic amplification or aberrant elevation are frequently observed in a variety of tumor types. Unlike protein-coding oncogenes, where one transcript produces one protein, mir-17-92 encodes a polycistronic miRNA transcript that yields six individual miRNA components. This unique gene structure, shared by many important miRNA oncogenes and tumor suppressors, underlies the unique functionality of mir-17-92 in a cell type and context-dependent manner. Recent functional dissection of mir-17-92 indicates that individual mir-17-92 components perform distinct biological functions, which collectively regulate multiple related cellular processes during development and disease. The structural complexity of mir-17-92 as a polycistronic miRNA oncogene, along with the complex mode of interactions among its components, constitutes the molecular basis for its unique functional complexity during normal and tumor development. © 2013 John Wiley & Sons A/S.

Authors
Olive, V; Li, Q; He, L
MLA Citation
Olive, V, Li, Q, and He, L. "mir-17-92: A polycistronic oncomir with pleiotropic functions." Immunological Reviews 253.1 (2013): 158-166.
PMID
23550645
Source
scival
Published In
Immunological Reviews
Volume
253
Issue
1
Publish Date
2013
Start Page
158
End Page
166
DOI
10.1111/imr.12054

Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression

BACKGROUND: A substantial percentage (10%-15%) of HIV-infected individuals experience a sharp decline in CD4μ T-cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) vs chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. METHODS: mRNAand microRNA (miRNA) expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111 (22) days [mean (SD)] of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by ROC analysis and Kaplan-Meier survival analysis. RESULTS: Pathway enrichment analysis showed that genes with deregulated expression in RPs were primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a, and -503) in RPs were significantly decreased compared to those in CPs (P<0.05). The decreased expression of these miRNAs was associated with a rapid disease of progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray analysis converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. CONCLUSIONS: Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection. © 2013 American Association for Clinical Chemistry.

Authors
Zhang, Z-N; Xu, J-J; Fu, Y-J; Liu, J; Jiang, Y-J; Cui, H-L; Zhao, B; Sun, H; He, Y-W; Li, Q-J; Shang, H
MLA Citation
Zhang, Z-N, Xu, J-J, Fu, Y-J, Liu, J, Jiang, Y-J, Cui, H-L, Zhao, B, Sun, H, He, Y-W, Li, Q-J, and Shang, H. "Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression." Clinical Chemistry 59.8 (2013): 1175-1186.
PMID
23592504
Source
scival
Published In
Clinical chemistry
Volume
59
Issue
8
Publish Date
2013
Start Page
1175
End Page
1186
DOI
10.1373/clinchem.2012.197335

A Single Peptide-Major Histocompatibility Complex Ligand Triggers Digital Cytokine Secretion in CD4+ T Cells

We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4+ T cell functional sensitivity. We found that naive T cells, T cell blasts, and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ∼1,000, ∼10,000, and ∼10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4+ T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell. © 2013 Elsevier Inc. All rights reserved.

Authors
Huang, J; Brameshuber, M; Zeng, X; Xie, J; Li, Q-J; Chien, Y-H; Valitutti, S; Davis, MM
MLA Citation
Huang, J, Brameshuber, M, Zeng, X, Xie, J, Li, Q-J, Chien, Y-H, Valitutti, S, and Davis, MM. "A Single Peptide-Major Histocompatibility Complex Ligand Triggers Digital Cytokine Secretion in CD4+ T Cells." Immunity (2013).
Source
scival
Published In
Immunity
Publish Date
2013
DOI
10.1016/j.immuni.2013.08.036

Transcriptional regulator Id2 is required for the CD4 T cell immune response in the development of experimental autoimmune encephalomyelitis.

An effective immune response to Ag challenge is critically dependent on the size of the effector cell population generated from clonal activation of Ag-specific T cells. The transcription network involved in regulating the size of the effector population, particularly for CD4 Th cells, is poorly understood. In this study, we investigate the role of Id2, an inhibitor of E protein transcription factors, in the generation of CD4 effectors. Using a T cell-specific conditional Id2 knockout mouse model, we show that inhibitor of DNA binding (Id)2 is essential for the development of experimental autoimmune encephalomyelitis. Although Ag-specific and IL-17-producing CD4 T cells are produced in these mice, the activated CD4 T cells form a smaller pool of effector cells in the peripheral lymphoid organs, exhibit reduced proliferation and increased cell death, and are largely absent in the CNS. In the absence of Id2, E protein targets, including the proapoptotic protein Bim and SOCS3, are expressed at higher levels among activated CD4 T cells. This study reveals a critical role of Id2 in the control of effector CD4 T cell population size and the development of a Th17-mediated autoimmune disease.

Authors
Lin, Y-Y; Jones-Mason, ME; Inoue, M; Lasorella, A; Iavarone, A; Li, Q-J; Shinohara, ML; Zhuang, Y
MLA Citation
Lin, Y-Y, Jones-Mason, ME, Inoue, M, Lasorella, A, Iavarone, A, Li, Q-J, Shinohara, ML, and Zhuang, Y. "Transcriptional regulator Id2 is required for the CD4 T cell immune response in the development of experimental autoimmune encephalomyelitis." J Immunol 189.3 (August 1, 2012): 1400-1405.
PMID
22745378
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
189
Issue
3
Publish Date
2012
Start Page
1400
End Page
1405
DOI
10.4049/jimmunol.1200491

Role of LAT in the granule-mediated cytotoxicity of CD8 T cells.

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is essential to bridge T cell receptor (TCR) engagement to downstream signaling events. The indispensable role of LAT in thymocyte development and T cell activation has been well characterized; however, the function of LAT in cytotoxic-T-lymphocyte (CTL) cytotoxicity remains unknown. We show here that LAT-deficient CTLs failed to upregulate FasL and produce gamma interferon after engagement with target cells and had impaired granule-mediated killing. We further dissected the effect of the LAT deletion on each step of granule exocytosis. LAT deficiency led to altered synapse formation, subsequently causing unstable T cell-antigen-presenting cell (APC) conjugates. Microtubule organizing center polarization and granule reorientation were also impaired by LAT deficiency, leading to reduced granule delivery. Despite these defects, granule release was still observed in LAT-deficient CTLs due to residual calcium flux and phospholipase C (PLC) activity. Our data demonstrated that LAT-mediated signaling intricately regulates CTL cytotoxicity at multiple steps.

Authors
Ou-Yang, C-W; Zhu, M; Fuller, DM; Sullivan, SA; Chuck, MI; Ogden, S; Li, Q-J; Zhang, W
MLA Citation
Ou-Yang, C-W, Zhu, M, Fuller, DM, Sullivan, SA, Chuck, MI, Ogden, S, Li, Q-J, and Zhang, W. "Role of LAT in the granule-mediated cytotoxicity of CD8 T cells." Mol Cell Biol 32.14 (July 2012): 2674-2684.
PMID
22566687
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
32
Issue
14
Publish Date
2012
Start Page
2674
End Page
2684
DOI
10.1128/MCB.00356-12

The Epstein-Barr virus (EBV)-induced tumor suppressor microrna MiR-34a is growth promoting in EBV-infected B cells

Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-κB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic-virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts. © 2012, American Society for Microbiology.

Authors
Forte, E; Salinas, RE; Chang, C; Zhou, T; Linnstaedt, SD; Gottwein, E; Jacobs, C; Jima, D; Li, Q-J; Dave, SS; Luftig, MA
MLA Citation
Forte, E, Salinas, RE, Chang, C, Zhou, T, Linnstaedt, SD, Gottwein, E, Jacobs, C, Jima, D, Li, Q-J, Dave, SS, and Luftig, MA. "The Epstein-Barr virus (EBV)-induced tumor suppressor microrna MiR-34a is growth promoting in EBV-infected B cells." Journal of Virology 86.12 (2012): 6889-6898.
PMID
22496226
Source
scival
Published In
Journal of virology
Volume
86
Issue
12
Publish Date
2012
Start Page
6889
End Page
6898
DOI
10.1128/JVI.07056-11

Photocrosslinkable pMHC monomers stain T cells specifically and cause ligand-bound TCRs to be 'preferentially' transported to the cSMAC

The binding of T cell antigen receptors (TCRs) to specific complexes of peptide and major histocompatibility complex (pMHC) is typically of very low affinity, which necessitates the use of multimeric pMHC complexes to label T lymphocytes stably. We report here the development of pMHC complexes able to be crosslinked by ultraviolet irradiation; even as monomers, these efficiently and specifically stained cognate T cells. We also used this reagent to probe T cell activation and found that a covalently bound pMHC was more stimulatory than an agonist pMHC on lipid bilayers. This finding suggested that serial engagement of TCRs is dispensable for activation when a substantial fraction of TCRs are stably engaged. Finally, pMHC-bound TCRs were 'preferentially' transported into the central supramolecular activation cluster after activation, which suggested that ligand engagement enabled linkage of the TCR and its associated CD3 signaling molecules to the cytoskeleton. © 2012 Nature America, Inc. All rights reserved.

Authors
Xie, J; Huppa, JB; Newell, EW; Huang, J; Ebert, PJR; Li, Q-J; Davis, MM
MLA Citation
Xie, J, Huppa, JB, Newell, EW, Huang, J, Ebert, PJR, Li, Q-J, and Davis, MM. "Photocrosslinkable pMHC monomers stain T cells specifically and cause ligand-bound TCRs to be 'preferentially' transported to the cSMAC." Nature Immunology 13.7 (2012): 674-680.
PMID
22660579
Source
scival
Published In
Nature Immunology
Volume
13
Issue
7
Publish Date
2012
Start Page
674
End Page
680
DOI
10.1038/ni.2344

Distinct CD4 + helper T cells involved in primary and secondary responses to infection

Helper T cells are critical for protective immunity, CD8 + T-cell memory, and CD4 + recall responses, but whether the same or distinct CD4 + T cells are involved in these responses has not been established. Here we describe two CD4 + T cells, LLO118 and LLO56, specific for an immunodominant Listeria monocytogenes epitope, with dramatically different responses to primary and secondary infection. Comparing in vivo responses, LLO118 T cells proliferate more strongly to primary infection, whereas surprisingly, LLO56 has a superior CD4 + recall response to secondary infection. LLO118 T cells provide more robust help for CD8 + T-cell responses to secondary infection than LLO56. We found no detectable differences in antigen sensitivity, but naive LLO118 T cells have much lower levels of CD5 and their T-cell receptor levels are dramatically down-regulated after their strong primary response. Thus, distinct CD4 + helper T cells are specialized to help either in primary or secondary responses to infection.

Authors
Weber, KS; Li, Q-J; Persaud, SP; Campbell, JD; Davis, MM; Allen, PM
MLA Citation
Weber, KS, Li, Q-J, Persaud, SP, Campbell, JD, Davis, MM, and Allen, PM. "Distinct CD4 + helper T cells involved in primary and secondary responses to infection." Proceedings of the National Academy of Sciences of the United States of America 109.24 (2012): 9511-9516.
PMID
22645349
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
24
Publish Date
2012
Start Page
9511
End Page
9516
DOI
10.1073/pnas.1202408109

TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma

Portal vein tumor thrombus (PVTT) is strongly correlated to a poor prognosis for patients with hepatocellular carcinoma (HCC). In this study, we uncovered a causative link between hepatitis B virus (HBV) infection and development of PVTT. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape. These findings strongly suggest that HBV infection and activity of the TGF-β-miR-34a-CCL22 axis serve as potent etiological factors to predispose HCC patients for the development of PVTT, possibly through the creation of an immune-subversive microenvironment to favor colonization of disseminated HCC cells in the portal venous system. © 2012 Elsevier Inc.

Authors
Yang, P; Li, Q-J; Feng, Y; Zhang, Y; Markowitz, GJ; Ning, S; Deng, Y; Zhao, J; Jiang, S; Yuan, Y; Wang, H-Y; Cheng, S-Q; Xie, D; Wang, X-F
MLA Citation
Yang, P, Li, Q-J, Feng, Y, Zhang, Y, Markowitz, GJ, Ning, S, Deng, Y, Zhao, J, Jiang, S, Yuan, Y, Wang, H-Y, Cheng, S-Q, Xie, D, and Wang, X-F. "TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma." Cancer Cell 22.3 (2012): 291-303.
PMID
22975373
Source
scival
Published In
Cancer Cell
Volume
22
Issue
3
Publish Date
2012
Start Page
291
End Page
303
DOI
10.1016/j.ccr.2012.07.023

Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation.

Mir-17-92 encodes 6 miRNAs inside a single polycistronic transcript, the proper expression of which is critical for early B-cell development and lymphocyte homeostasis. However, during the T-cell antigen response, the physiologic function of endogenous miR-17-92 and the roles of the individual miRNAs remain elusive. In the present study, we functionally dissected the miR-17-92 cluster and revealed that miR-17 and miR-19b are the key players controlling Th1 responses through multiple coordinated biologic processes. These include: promoting proliferation, protecting cells from activation-induced cell death, supporting IFN-γ production, and suppressing inducible regulatory T-cell differentiation. Mechanistically, we identified Pten (phosphatase and tensin homolog) as the functionally important target of miR-19b, whereas the function of miR-17 is mediated by TGFβRII and the novel target CREB1. Because of its vigorous control over the Th1 cell-inducible regulatory T cell balance, the loss of miR-17-92 in CD4 T cells results in tumor evasion. Our results suggest that miR-19b and miR-17 could be harnessed to enhance the efficacy of T cell-based tumor therapy.

Authors
Jiang, S; Li, C; Olive, V; Lykken, E; Feng, F; Sevilla, J; Wan, Y; He, L; Li, Q-J
MLA Citation
Jiang, S, Li, C, Olive, V, Lykken, E, Feng, F, Sevilla, J, Wan, Y, He, L, and Li, Q-J. "Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation." Blood 118.20 (November 17, 2011): 5487-5497.
PMID
21972292
Source
pubmed
Published In
Blood
Volume
118
Issue
20
Publish Date
2011
Start Page
5487
End Page
5497
DOI
10.1182/blood-2011-05-355644

The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression.

IL-7Rα-mediated signals are essential for naive T lymphocyte survival. Recent studies show that IL-7Rα is internalized and either recycled to cell surface or degraded. However, how the intracellular process of IL-7Rα trafficking is regulated is unclear. In this paper, we show that Vps34, the class III PI3K, plays a critical role in proper IL-7Rα intracellular trafficking. Mice lacking Vps34 in T lymphocytes had a severely reduced T lymphocyte compartment. Vps34-deficient T lymphocytes exhibit increased death and reduced IL-7Rα surface expression, although three major forms of autophagy remain intact. Intracellular IL-7Rα in normal T lymphocytes at steady state is trafficked through either early endosome/multivesicular bodies to the late endosome-Golgi for surface expression or to the lysosome for degradation. However, Vps34-deficient T cells have mislocalized intracellular Eea1, HGF-regulated tyrosine kinase substrate, and Vps36 protein levels, the combined consequence of which is the inability to mobilize internalized IL-7Rα into the retromer pathway for surface display. Our studies reveal that Vps34, though dispensable for autophagy induction, is a critical regulator of naive T cell homeostasis, modulating IL-7Rα trafficking, signaling, and recycling.

Authors
McLeod, IX; Zhou, X; Li, Q-J; Wang, F; He, Y-W
MLA Citation
McLeod, IX, Zhou, X, Li, Q-J, Wang, F, and He, Y-W. "The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression." J Immunol 187.10 (November 15, 2011): 5051-5061.
PMID
22021616
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
187
Issue
10
Publish Date
2011
Start Page
5051
End Page
5061
DOI
10.4049/jimmunol.1100710

Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes.

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular bulk degradation pathway that plays critical roles in eliminating intracellular pathogens, presenting endogenous Ags, and regulating T lymphocyte survival and proliferation. In this study, we have investigated the role of autophagy in regulating the endoplasmic reticulum (ER) compartment in T lymphocytes. We found that ER content is expanded in mature autophagy-related protein (Atg) 7-deficient T lymphocytes. Atg7-deficient T cells stimulated through the TCR display impaired influx, but not efflux, of calcium, and ER calcium stores are increased in Atg7-deficient T cells. Treatment with the ER sarco/ER Ca(2+)-ATPase pump inhibitor thapsigargin rescues the calcium influx defect in Atg7-deficient T lymphocytes, suggesting that this impairment is caused by an intrinsic defect in ER. Furthermore, we found that the stimulation-induced redistribution of stromal interaction molecule-1, a critical event for the store-operated Ca(2+) release-activated Ca(2+) channel opening, is impaired in Atg7-deficient T cells. Together, these findings indicate that the expanded ER compartment in Atg7-deficient T cells contains increased calcium stores, and the inability of these stores to be depleted causes defective calcium influx in these cells. Our results demonstrate that autophagy plays an important role in maintaining ER and calcium homeostasis in T lymphocytes.

Authors
Jia, W; Pua, HH; Li, Q-J; He, Y-W
MLA Citation
Jia, W, Pua, HH, Li, Q-J, and He, Y-W. "Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes." J Immunol 186.3 (February 1, 2011): 1564-1574.
PMID
21191072
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
186
Issue
3
Publish Date
2011
Start Page
1564
End Page
1574
DOI
10.4049/jimmunol.1001822

Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells

Prostate cancer is the second leading cause of cancer-related deaths among US males. Pomegranate juice (PJ), a natural product, was shown in a clinical trial to inhibit progression of this disease. However, the underlying mechanisms involved in the anti-progression effects of PJ on prostate cancer remain unclear. Here we show that, in addition to causing cell death of hormone-refractory prostate cancer cells, PJ also increases cell adhesion and decreases cell migration of the cells that do not die. We hypothesized that PJ does so by stimulating the expression and/or activation of molecules that alter the cytoskeleton and the adhesion machinery of prostate cancer cells, resulting in enhanced cell adhesion and reduced cell migration. We took an integrative approach to these studies by using Affimetrix gene arrays to study gene expression, microRNA arrays to study the non-coding RNAs, molecules known to be disregulated in cancer cells, and Luminex Multiplex array assays to study the level of secreted pro-inflammatory cytokines/chemokines. PJ up-regulates genes involved in cell adhesion such as E-cadherin, intercellular adhesion molecule 1 (ICAM-1) and down-regulates genes involved in cell migration such as hyaluranan-mediated motility receptor (HMMR) and type I collagen. In addition, anti-invasive microRNAs such as miR-335, miR-205, miR-200, and miR-126, were up-regulated, whereas pro-invasive microRNA such as miR-21 and miR-373, were down-regulated. Moreover, PJ significantly reduced the level of secreted pro-inflammatory cytokines/chemokines such as IL-6, IL-12p40, IL-1β and RANTES, thereby having the potential to decrease inflammation and its impact on cancer progression. PJ also inhibits the ability of the chemokine SDF1α to chemoattract these cancer cells. SDF1α and its receptor CXCR4 are important in metastasis of cancer cells to the bone. Discovery of the mechanisms by which this enhanced adhesion and reduced migration are accomplished can lead to sophisticated and effective prevention of metastasis in prostate and potentially other cancers. © 2011 The Royal Society of Chemistry.

Authors
Wang, L; Alcon, A; Yuan, H; Ho, J; Li, Q-J; Martins-Green, M
MLA Citation
Wang, L, Alcon, A, Yuan, H, Ho, J, Li, Q-J, and Martins-Green, M. "Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells." Integrative Biology 3.7 (2011): 742-754.
PMID
21594291
Source
scival
Published In
Integrative Biology
Volume
3
Issue
7
Publish Date
2011
Start Page
742
End Page
754
DOI
10.1039/c0ib00122h

microRNAs at the regulatory frontier: An investigation into how microRNAs impact the development and effector functions of CD4 T cells

CD4 T cells are an integral part of adaptive immunity. microRNAs have been identified as fundamental regulators of post-transcriptional programs and to play roles in T lymphocytes' development, differentiation, and effector functions. To better understand the role of miRNAs in T cells and to identify potential therapeutic tools and targets, we have undertaken studies of miRNAs that modulate or are modulated by T-cell receptor signaling. We identified miR-181a as a key regulator of TCR signaling strength, and hence T-cell development, and the miR-17-92 cluster as an important player in CD4 T cells' response against antigens. These discoveries, coupled with work by other researchers, reveal the power and importance of miRNA-mediated regulation in T-cell responses and offer new insights into the burgeoning field of immunoregulation. © 2010 Springer Science+Business Media, LLC.

Authors
Lykken, EA; Li, Q-J
MLA Citation
Lykken, EA, and Li, Q-J. "microRNAs at the regulatory frontier: An investigation into how microRNAs impact the development and effector functions of CD4 T cells." Immunologic Research 49.1-3 (2011): 87-96.
PMID
21191665
Source
scival
Published In
Immunologic Research
Volume
49
Issue
1-3
Publish Date
2011
Start Page
87
End Page
96
DOI
10.1007/s12026-010-8196-4

Functional development of the T cell receptor for antigen

For over three decades now, the T cell receptor (TCR) for antigen has not ceased to challenge the imaginations of cellular and molecular immunologists alike. T cell antigen recognition transcends every aspect of adaptive immunity: it shapes the T cell repertoire in the thymus and directs T cell-mediated effector functions in the periphery, where it is also central to the induction of peripheral tolerance. Yet, despite its central position, there remain many questions unresolved: how can one TCR be specific for one particular peptide-major histocompatibility complex (pMHC) ligand while also binding other pMHC ligands with an immunologically relevant affinity? And how can a T cell's extreme specificity (alterations of single methyl groups in their ligand can abrogate a response) and sensitivity (single agonist ligands on a cell surface are sufficient to trigger a measurable response) emerge from TCRligand interactions that are so low in affinity? Solving these questions is intimately tied to a fundamental understanding of molecular recognition dynamics within the many different contexts of various T cellantigen presenting cell (APC) contacts: from the thymic APCs that shape the TCR repertoire and guide functional differentiation of developing T cells to the peripheral APCs that support homeostasis and provoke antigen responses in nave, effector, memory, and regulatory T cells. Here, we discuss our recent findings relating to T cell antigen recognition and how this leads to the thymic development of foreign-antigen-responsive αβT cells. © 2010 Elsevier Inc. All rights reserved.

Authors
Ebert, PJR; Li, Q-J; Huppa, JB; Davis, MM
MLA Citation
Ebert, PJR, Li, Q-J, Huppa, JB, and Davis, MM. "Functional development of the T cell receptor for antigen." Progress in Molecular Biology and Translational Science 92.C (2010): 65-100.
PMID
20800817
Source
scival
Published In
Progress in Molecular Biology and Translational Science
Volume
92
Issue
C
Publish Date
2010
Start Page
65
End Page
100
DOI
10.1016/S1877-1173(10)92004-8

miR-19 is a key oncogenic component of mir-17-92.

Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Emu-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt-mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.

Authors
Olive, V; Bennett, MJ; Walker, JC; Ma, C; Jiang, I; Cordon-Cardo, C; Li, Q-J; Lowe, SW; Hannon, GJ; He, L
MLA Citation
Olive, V, Bennett, MJ, Walker, JC, Ma, C, Jiang, I, Cordon-Cardo, C, Li, Q-J, Lowe, SW, Hannon, GJ, and He, L. "miR-19 is a key oncogenic component of mir-17-92." Genes Dev 23.24 (December 15, 2009): 2839-2849.
PMID
20008935
Source
pubmed
Published In
Genes & development
Volume
23
Issue
24
Publish Date
2009
Start Page
2839
End Page
2849
DOI
10.1101/gad.1861409

An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a.

Thymic positive selection is based on the interactions of T cell antigen receptors (TCRs) with self peptide-major histocompatibility complex (MHC) ligands, but the identity of selecting peptides for MHC class II-restricted TCRs and the functional consequences of this peptide specificity are not clear. Here we identify several endogenous self peptides that positively selected the MHC class II-restricted 5C.C7 TCR. The most potent of these also enhanced mature T cell activation, which supports the hypothesis that one function of positive selection is to produce T cells that can use particular self peptide-MHC complexes for activation and/or homeostasis. We also show that inhibiting the microRNA miR-181a resulted in maturation of T cells that overtly reacted toward these erstwhile positively selecting peptides. Therefore, miR-181a helps to guarantee the clonal deletion of particular moderate-affinity clones by modulating the TCR signaling threshold of thymocytes.

Authors
Ebert, PJR; Jiang, S; Xie, J; Li, Q-J; Davis, MM
MLA Citation
Ebert, PJR, Jiang, S, Xie, J, Li, Q-J, and Davis, MM. "An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a." Nat Immunol 10.11 (November 2009): 1162-1169.
PMID
19801983
Source
pubmed
Published In
Nature Immunology
Volume
10
Issue
11
Publish Date
2009
Start Page
1162
End Page
1169
DOI
10.1038/ni.1797

The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment.

Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.

Authors
Yu, D; Rao, S; Tsai, LM; Lee, SK; He, Y; Sutcliffe, EL; Srivastava, M; Linterman, M; Zheng, L; Simpson, N; Ellyard, JI; Parish, IA; Ma, CS; Li, Q-J; Parish, CR; Mackay, CR; Vinuesa, CG
MLA Citation
Yu, D, Rao, S, Tsai, LM, Lee, SK, He, Y, Sutcliffe, EL, Srivastava, M, Linterman, M, Zheng, L, Simpson, N, Ellyard, JI, Parish, IA, Ma, CS, Li, Q-J, Parish, CR, Mackay, CR, and Vinuesa, CG. "The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment." Immunity 31.3 (September 18, 2009): 457-468.
PMID
19631565
Source
pubmed
Published In
Immunity
Volume
31
Issue
3
Publish Date
2009
Start Page
457
End Page
468
DOI
10.1016/j.immuni.2009.07.002

The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-alpha motif domain in thymic selection and T-cell activation.

The Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76) is a cytosolic adaptor protein essential for thymocyte development and T-cell activation. It contains a sterile-alpha motif (SAM) domain, 3 phosphotyrosine motifs, a proline-rich region, and a Src homology 2 domain. Whereas the other domains have been extensively studied, the role of the SAM domain in SLP-76 function is not known. To understand the function of this domain, we generated SLP-76 knockin mice with the SAM domain deleted. Analysis of these mice showed that thymocyte development was partially blocked at the double-positive to single-positive transition. Positive and negative thymic selection was also impaired. In addition, we analyzed T-cell receptor (TCR)-mediated signaling in T cells from these mutant mice. TCR-mediated inositol 1,4,5-triphosphate production, calcium flux, and extracellular signal-regulated kinase activation were decreased, leading to defective interleukin-2 production and proliferation. Moreover, despite normal association between Gads and SLP-76, TCR-mediated formation of SLP-76 microclusters was impaired by the deletion of the SAM domain. Altogether, our data demonstrated that the SAM domain is indispensable for optimal SLP-76 signaling.

Authors
Shen, S; Lau, J; Zhu, M; Zou, J; Fuller, D; Li, Q-J; Zhang, W
MLA Citation
Shen, S, Lau, J, Zhu, M, Zou, J, Fuller, D, Li, Q-J, and Zhang, W. "The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-alpha motif domain in thymic selection and T-cell activation." Blood 114.1 (July 2, 2009): 74-84.
PMID
19401562
Source
pubmed
Published In
Blood
Volume
114
Issue
1
Publish Date
2009
Start Page
74
End Page
84
DOI
10.1182/blood-2008-09-177832

Spatial and temporal dynamics of T cell receptor signaling with a photoactivatable agonist.

The precise timing of signals downstream of the T cell receptor (TCR) is poorly understood. To address this problem, we prepared major histocompatibility complexes containing an antigenic peptide that is biologically inert until exposed to ultraviolet (UV) light. UV irradiation of these complexes in contact with cognate T cells enabled the high-resolution temporal analysis of signaling. Phosphorylation of the LAT adaptor molecule was observed in 4 s, and diacylglycerol production and calcium flux was observed in 6-7 s. TCR activation also induced cytoskeletal polarization within 2 min. Antibody blockade of CD4 reduced the intensity of LAT phosphorylation and the speed of calcium flux. Furthermore, strong desensitization of diacylglycerol production, but not LAT phosphorylation, occurred shortly after TCR activation, suggesting that different molecular events play distinct signal-processing roles. These results establish the speed and localization of early signaling steps, and have important implications regarding the overall structure of the network.

Authors
Huse, M; Klein, LO; Girvin, AT; Faraj, JM; Li, Q-J; Kuhns, MS; Davis, MM
MLA Citation
Huse, M, Klein, LO, Girvin, AT, Faraj, JM, Li, Q-J, Kuhns, MS, and Davis, MM. "Spatial and temporal dynamics of T cell receptor signaling with a photoactivatable agonist." Immunity 27.1 (July 2007): 76-88.
PMID
17629516
Source
pubmed
Published In
Immunity
Volume
27
Issue
1
Publish Date
2007
Start Page
76
End Page
88
DOI
10.1016/j.immuni.2007.05.017

miR-181a is an intrinsic modulator of T cell sensitivity and selection.

T cell sensitivity to antigen is intrinsically regulated during maturation to ensure proper development of immunity and tolerance, but how this is accomplished remains elusive. Here we show that increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, while inhibiting miR-181a expression in the immature T cells reduces sensitivity and impairs both positive and negative selection. Moreover, quantitative regulation of T cell sensitivity by miR-181a enables mature T cells to recognize antagonists-the inhibitory peptide antigens-as agonists. These effects are in part achieved by the downregulation of multiple phosphatases, which leads to elevated steady-state levels of phosphorylated intermediates and a reduction of the T cell receptor signaling threshold. Importantly, higher miR-181a expression correlates with greater T cell sensitivity in immature T cells, suggesting that miR-181a acts as an intrinsic antigen sensitivity "rheostat" during T cell development.

Authors
Li, Q-J; Chau, J; Ebert, PJR; Sylvester, G; Min, H; Liu, G; Braich, R; Manoharan, M; Soutschek, J; Skare, P; Klein, LO; Davis, MM; Chen, C-Z
MLA Citation
Li, Q-J, Chau, J, Ebert, PJR, Sylvester, G, Min, H, Liu, G, Braich, R, Manoharan, M, Soutschek, J, Skare, P, Klein, LO, Davis, MM, and Chen, C-Z. "miR-181a is an intrinsic modulator of T cell sensitivity and selection." Cell 129.1 (April 6, 2007): 147-161.
PMID
17382377
Source
pubmed
Published In
Cell
Volume
129
Issue
1
Publish Date
2007
Start Page
147
End Page
161
DOI
10.1016/j.cell.2007.03.008

T cells as a self-referential, sensory organ.

In light of recent data showing that both helper and cytotoxic T cells can detect even a single molecule of an agonist peptide-MHC, alphabeta T cells are clearly a type of sensory cell, comparable to any in the nervous system. In addition, endogenous (self) peptides bound to MHCs are not just important for thymic selection, but also play an integral role in T cell activation in the response to foreign antigens. With the multitude of specificities available to most T cells, they can thus be considered as a sensory organ, trained on self-peptide-MHCs and primed to detect nonself.

Authors
Davis, MM; Krogsgaard, M; Huse, M; Huppa, J; Lillemeier, BF; Li, Q-J
MLA Citation
Davis, MM, Krogsgaard, M, Huse, M, Huppa, J, Lillemeier, BF, and Li, Q-J. "T cells as a self-referential, sensory organ." Annu Rev Immunol 25 (2007): 681-695. (Review)
PMID
17291190
Source
pubmed
Published In
Annual Review of Immunology
Volume
25
Publish Date
2007
Start Page
681
End Page
695
DOI
10.1146/annurev.immunol.24.021605.090600

Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity.

Alphabeta T lymphocytes are able to detect even a single peptide-major histocompatibility complex (MHC) on the surface of an antigen-presenting cell. This is despite clear evidence, at least with CD4+ T cells, that monomeric ligands are not stimulatory. In an effort to understand how this remarkable sensitivity is achieved, we constructed soluble peptide-MHC heterodimers in which one peptide is an agonist and the other is one of the large number of endogenous peptide-MHCs displayed by presenting cells. We found that some specific combinations of these heterodimers can stimulate specific T cells in a CD4-dependent manner. This activation is severely impaired if the CD4-binding site on the agonist ligand is ablated, but the same mutation on an endogenous ligand has no effect. These data correlate well with analyses of lipid bilayers and cells presenting these ligands, and indicate that the basic unit of helper T cell activation is a heterodimer of agonist peptide- and endogenous peptide-MHC complexes, stabilized by CD4.

Authors
Krogsgaard, M; Li, Q-J; Sumen, C; Huppa, JB; Huse, M; Davis, MM
MLA Citation
Krogsgaard, M, Li, Q-J, Sumen, C, Huppa, JB, Huse, M, and Davis, MM. "Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity." Nature 434.7030 (March 10, 2005): 238-243.
PMID
15724150
Source
pubmed
Published In
Nature
Volume
434
Issue
7030
Publish Date
2005
Start Page
238
End Page
243
DOI
10.1038/nature03391

cCXCR1 is a receptor for cIL-8 (9E3/cCAF) and its N- and C-terminal peptides and is also activated by hIL-8 (CXCL8).

Chemokines are chemotactic cytokines that play important roles in immune responses and wound healing, as well as in pathological conditions such as chronic inflammation and tumorigenesis. The chemokines and their receptors are highly conserved and maintain similar functions in different species. One noteworthy exception is the chemokine interleukin (IL)8/CXC ligand 8 and its specific receptor CXCR1, which are found in humans but are not found in the traditional model organisms, mice and rats. As a consequence, we are using model organisms other than mice to study the functions of IL-8 and CXCR1, as well as the mechanisms involved in receptor activation by IL-8. Toward this goal, we have isolated and characterized a new receptor that is highly homologous to human (h)CXCR1, which we named chicken (c)CXCR1. To determine whether this receptor is activated by cIL-8 and its N- and C-terminal peptides and whether it responds to hIL-8, we expressed cCXCR1 in NIH3T3 cells, which naturally lack this receptor, and used single-cell Ca(2)(+) imaging to detect increases in intracellular Ca(2)(+) and immunoblot analysis to detect extracellular signal-regulated kinase 1/2 phosphorylation. We show that cIL-8, its N and C peptides, and hIL-8 activate cCXCR1. We further show that cIL-8 and hIL-8 stimulate chemotaxis of chicken embryonic fibroblasts, cells that express cCXCR1, and that this effect is specific for each chemokine and this receptor. These results strongly suggest that cCXCR1 is the ortholog for hCXCR1 and that chickens can be used as an effective model system to study the functions of IL-8, its terminal peptides, and its specific receptor CXCR1.

Authors
Li, Q-J; Yao, M; Dueck, M; Feugate, JE; Parpura, V; Martins-Green, M
MLA Citation
Li, Q-J, Yao, M, Dueck, M, Feugate, JE, Parpura, V, and Martins-Green, M. "cCXCR1 is a receptor for cIL-8 (9E3/cCAF) and its N- and C-terminal peptides and is also activated by hIL-8 (CXCL8)." J Leukoc Biol 77.3 (March 2005): 421-431.
PMID
15576419
Source
pubmed
Published In
Journal of leukocyte biology
Volume
77
Issue
3
Publish Date
2005
Start Page
421
End Page
431
DOI
10.1189/jlb.0704398

A new generation organ culture arising from cross-talk between multiple primary human cell types.

The inability to experiment directly on humans strongly constrains biomedical research, creating a great need to develop cultures that mimic human tissues and organs as experimental systems that can be used to directly understand and manipulate biological processes. The advent of availability of primary human cells now makes possible engineering of such organ cultures. Here we report the generation of a human "skin" arguably the simplest human tissue. Beginning with three primary cell types taken from adult tissues, this organ culture develops into a mature tissue containing a stratified epithelium and an interconnected network of mature microvessels, with appropriate matrix molecules and cytokines. Surprisingly, pericytes and monocytes appear adjacent to and within "blood" vessels, respectively. These cultures respond appropriately to stimulators of specific biological processes, providing a vehicle to investigate basic biological processes, such as 1) cell-cell and cell-microenvironment interaction; 2) transdifferentiation of one cell type to another and/or differentiation from stem cells present in adult tissues; and 3) opportunities for genetic manipulation of human tissues to understand function. Moreover, this "skin" can potentially be developed into a tailored "living bandage" for patients with impaired healing and can serve as prototype for the development of other human organ cultures.

Authors
Martins-Green, M; Li, Q-J; Yao, M
MLA Citation
Martins-Green, M, Li, Q-J, and Yao, M. "A new generation organ culture arising from cross-talk between multiple primary human cell types." FASEB J 19.2 (February 2005): 222-224.
PMID
15591154
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
19
Issue
2
Publish Date
2005
Start Page
222
End Page
224
DOI
10.1096/fj.04-1725fje

CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse.

How T cells respond with extraordinary sensitivity to minute amounts of agonist peptide and major histocompatibility complex (pMHC) molecules on the surface of antigen-presenting cells bearing large numbers of endogenous pMHC molecules is not understood. Here we present evidence that CD4 affects the responsiveness of T helper cells by controlling spatial localization of the tyrosine kinase Lck in the synapse. This finding, as well as further in silico and in vitro experiments, led us to develop a molecular model in which endogenous and agonist pMHC molecules act cooperatively to amplify T cell receptor signaling. At the same time, activation due to endogenous pMHC molecules alone is inhibited. A key feature is that the binding of agonist pMHC molecules to the T cell receptor results in CD4-mediated spatial localization of Lck, which in turn enables endogenous pMHC molecules to trigger many T cell receptors. We also discuss broader implications for T cell biology, including thymic selection, diversity of the repertoire of self pMHC molecules and serial triggering.

Authors
Li, Q-J; Dinner, AR; Qi, S; Irvine, DJ; Huppa, JB; Davis, MM; Chakraborty, AK
MLA Citation
Li, Q-J, Dinner, AR, Qi, S, Irvine, DJ, Huppa, JB, Davis, MM, and Chakraborty, AK. "CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse." Nat Immunol 5.8 (August 2004): 791-799.
PMID
15247914
Source
pubmed
Published In
Nature Immunology
Volume
5
Issue
8
Publish Date
2004
Start Page
791
End Page
799
DOI
10.1038/ni1095

The N- and C-terminal peptides of hIL8/CXCL8 are ligands for hCXCR1 and hCXCR2.

Chemokines are small cytokines that function in immune responses, wound healing, and pathological conditions such as chronic inflammation and tumorigenesis. This multifunctionality has been attributed primarily to ligand interaction with multiple or dimerized receptors. However, multifunctionality could also result from interactions of the receptors with small peptides produced by processing of the chemokines. Chemokine peptides are functional in vivo, but it is not yet known whether they can interact with and activate their receptors. The work presented here examines the interactions between the two forms of human interleukin 8 (hIL-8), and its N- and C-peptides, with the chemokine receptors hCXCR1 and hCXCR2. We used a Tet-on retroviral system to introduce CXCR1 into mouse NIH 3T3 cells (that lack endogenous CXCR1) and monitored activation of this receptor by the ligands by using quantitative Ca2+ imaging and mitogen-activated protein kinase (MAPK) activation. We found that the N and C termini of the chemokine can stimulate the respective CXCR1 to induce intracellular Ca2+ release and MAPK activation independent of the other regions of the molecules. Furthermore, we showed that these peptides can also stimulate chemotaxis of several cell types, including primary human microvascular endothelial cells, and that this function is specific and mediated by hCXCR1 and/or hCXCR2. These findings advance understanding of the multifunctionality exhibited by chemokines, reveal a new mode of functional regulation, and may serve as the basis for therapeutic targeting.

Authors
Li, Q-J; Yao, M; Wong, W; Parpura, V; Martins-Green, M
MLA Citation
Li, Q-J, Yao, M, Wong, W, Parpura, V, and Martins-Green, M. "The N- and C-terminal peptides of hIL8/CXCL8 are ligands for hCXCR1 and hCXCR2." FASEB J 18.6 (April 2004): 776-778.
PMID
14766805
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
18
Issue
6
Publish Date
2004
Start Page
776
End Page
778
DOI
10.1096/fj.02-1175fje

Histochemical localization of the PBAN receptor in the pheromone gland of Heliothis peltigera.

The presence of the pyrokinin (PK)/ Pheromone biosynthesis activating neuropeptide (PBAN) receptor in pheromone gland cells of Heliothis peltigera females was demonstrated, and its spatial distribution in the ovipositor was visualized with two photo-affinity biotinilated ligands: BpaPBAN1-33NH(2) and BpaArg(27)-PBAN28-33NH(2). Light microscopy histological studies revealed that the gland is contained within the inter-segmental membrane (ISM) between the 8th and 9th abdominal segments. The gland was found to be composed of a single layer of columnar epithelial cells positioned under the inter-segmental cuticle. Similar epithelial cells were also found in the dorsal and ventral regions of the 9th abdominal segment. All regions containing the glandular cells bound both ligands, indicating presence of the PK/PBAN receptor. The patterns obtained with both ligands were similar, hinting at the possibility that either both ligands bind to the same receptor, or, that if there are two distinct receptors, their spatial distribution throughout the gland is very similar.

Authors
Altstein, M; Ben-Aziz, O; Bhargava, K; Li, Q; Martins-Green, M
MLA Citation
Altstein, M, Ben-Aziz, O, Bhargava, K, Li, Q, and Martins-Green, M. "Histochemical localization of the PBAN receptor in the pheromone gland of Heliothis peltigera." Peptides 24.9 (September 2003): 1335-1347.
PMID
14706548
Source
pubmed
Published In
Peptides
Volume
24
Issue
9
Publish Date
2003
Start Page
1335
End Page
1347

MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300.

CBP/p300 recruitment to enhancer-bound complexes is a key determinant in promoter activation by many transcription factors. We present a novel mechanism of activating such complexes and show that pre-assembled Elk-1-p300 complexes become activated following Elk-1 phosphorylation by changes in Elk-1-p300 interactions rather than recruitment. It is known that Elk-1 binds to promoter in the absence of stimuli. However, it is unclear how activation of Elk-1 by mitogen-acivated protein kinase (MAPK)-mediated phosphorylation leads to targeted gene transactivation. We show that Elk-1 can interact with p300 in vitro and in vivo in the absence of a stimulus through the Elk-1 C-terminus and the p300 N-terminus. Phosphorylation on Ser383 and Ser389 of Elk-1 by MAPK enhances this basal binding but, most importantly, Elk-1 exhibits new interactions with p300. These interaction changes render a strong histone acetyltransferase activity in the Elk-1-associated complex that could play a critical role in chromatin remodeling and gene activation. The pre-assembly mechanism may greatly accelerate transcription activation, which is important in regulation of expression of immediate-early response genes, in particular those involved in stress responses.

Authors
Li, Q-J; Yang, S-H; Maeda, Y; Sladek, FM; Sharrocks, AD; Martins-Green, M
MLA Citation
Li, Q-J, Yang, S-H, Maeda, Y, Sladek, FM, Sharrocks, AD, and Martins-Green, M. "MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300." EMBO J 22.2 (January 15, 2003): 281-291.
PMID
12514134
Source
pubmed
Published In
EMBO Journal
Volume
22
Issue
2
Publish Date
2003
Start Page
281
End Page
291
DOI
10.1093/emboj/cdg028

The CXC chemokine cCAF stimulates precocious deposition of ECM molecules by wound fibroblasts, accelerating development of granulation tissue.

BACKGROUND: During wound repair, fibroblasts orchestrate replacement of the provisional matrix formed during clotting with tenascin, cellular fibronectin and collagen III. These, in turn, are critical for migration of endothelial cells, keratinocytes and additional fibroblasts into the wound site. Fibroblasts are also important in the deposition of collagen I during scar formation. The CXC chemokine chicken Chemotactic and Angiogenic Factor (cCAF), is highly expressed by fibroblasts after wounding and during development of the granulation tissue, especially in areas where extracellular matrix (ECM) is abundant. We hypothesized that cCAF stimulates fibroblasts to produce these matrix molecules. RESULTS: Here we show that this chemokine can stimulate precocious deposition of tenascin, fibronectin and collagen I, but not collagen III. Studies in culture and in vivo show that tenascin stimulation can also be achieved by the N-terminal 15 aas of the protein and occurs at the level of gene expression. In contrast, stimulation of fibronectin and collagen I both require the entire molecule and do not involve changes in gene expression. Fibronectin accumulation appears to be linked to tenascin production, and collagen I to decreased MMP-1 levels. In addition, cCAF is chemotactic for fibroblasts and accelerates their migration. CONCLUSIONS: These previously unknown functions for chemokines suggest that cCAF, the chicken orthologue of human IL-8, enhances healing by rapidly chemoattracting fibroblasts into the wound site and stimulating them to produce ECM molecules, leading to precocious development of granulation tissue. This acceleration of the repair process may have important application to healing of impaired wounds.

Authors
Feugate, JE; Wong, L; Li, Q-J; Martins-Green, M
MLA Citation
Feugate, JE, Wong, L, Li, Q-J, and Martins-Green, M. "The CXC chemokine cCAF stimulates precocious deposition of ECM molecules by wound fibroblasts, accelerating development of granulation tissue. (Published online)" BMC Cell Biol 3 (June 10, 2002): 13-.
PMID
12057014
Source
pubmed
Published In
BMC Cell Biology
Volume
3
Publish Date
2002
Start Page
13

The cxc chemokine cCAF stimulates differentiation of fibroblasts into myofibroblasts and accelerates wound closure.

Chemokines are small cytokines primarily known for their roles in inflammation. More recently, however, they have been implicated in processes involved in development of the granulation tissue of wounds, but little is known about their functions during this process. Fibroblasts play key roles in this phase of healing: some fibroblasts differentiate into myofibroblasts, alpha-smooth muscle actin (SMA)-producing cells that are important in wound closure and contraction. Here we show that the CXC chemokine chicken chemotactic and angiogenic factor (cCAF) stimulates fibroblasts to produce high levels of alpha-SMA and to contract collagen gels more effectively than do normal fibroblasts, both characteristic properties of myofibroblasts. Specific inhibition of alpha-SMA expression resulted in abrogation of cCAF-induced contraction. Furthermore, application of cCAF to wounds in vivo increases the number of myofibroblasts present in the granulation tissue and accelerates wound closure and contraction. We also show that these effects in culture and in vivo can be achieved by a peptide containing the NH2-terminal 15 amino acids of the cCAF protein and that inhibition of alpha-SMA expression also results in inhibition of N-peptide-induced collagen gel contraction. We propose that chemokines are major contributors for the differentiation of fibroblasts into myofibroblasts during formation of the repair tissue. Because myofibroblasts are important in many pathological conditions, and because chemokines and their receptors are amenable to pharmacological manipulations, chemokine stimulation of myofibroblast differentiation may have implications for modulation of functions of these cells in vivo.

Authors
Feugate, JE; Li, Q; Wong, L; Martins-Green, M
MLA Citation
Feugate, JE, Li, Q, Wong, L, and Martins-Green, M. "The cxc chemokine cCAF stimulates differentiation of fibroblasts into myofibroblasts and accelerates wound closure." J Cell Biol 156.1 (January 7, 2002): 161-172.
PMID
11781340
Source
pubmed
Published In
The Journal of Cell Biology
Volume
156
Issue
1
Publish Date
2002
Start Page
161
End Page
172
DOI
10.1083/jcb.200103062

The CXC chemokine cCAF stimulates precocious deposition of ECM molecules by wound fibroblasts, accelerating development of granulation tissue

Background: During wound repair, fibroblasts orchestrate replacement of the provisional matrix formed during clotting with tenascin, cellular fibronectin and collagen III. These, in turn, are critical for migration of endothelial cells, keratinocytes and additional fibroblasts into the wound site. Fibroblasts are also important in the deposition of collagen I during scar formation. The CXC chemokine chicken Chemotactic and Angiogenic Factor (cCAF), is highly expressed by fibroblasts after wounding and during development of the granulation tissue, especially in areas where extracellular matrix (ECM) is abundant. We hypothesized that cCAF stimulates fibroblasts to produce these matrix molecules. Results: Here we show that this chemokine can stimulate precocious deposition of tenascin, fibronectin and collagen I, but not collagen III. Studies in culture and in vivo show that tenascin stimulation can also be achieved by the N-terminal 15 aas of the protein and occurs at the level of gene expression. In contrast, stimulation of fibronectin and collagen I both require the entire molecule and do not involve changes in gene expression. Fibronectin accumulation appears to be linked to tenascin production, and collagen I to decreased MMP-1 levels. In addition, cCAF is chemotactic for fibroblasts and accelerates their migration. Conclusions: These previously unknown functions for chemokines suggest that cCAF, the chicken orthologue of human IL-8, enhances healing by rapidly chemoattracting fibroblasts into the wound site and stimulating them to produce ECM molecules, leading to precocious development of granulation tissue. This acceleration of the repair process may have important application to healing of impaired wounds. © 2002 Feugate et al; licensee BioMed Central Ltd.

Authors
Feugate, JE; Wong, L; Li, Q-J; Martins-Green, M
MLA Citation
Feugate, JE, Wong, L, Li, Q-J, and Martins-Green, M. "The CXC chemokine cCAF stimulates precocious deposition of ECM molecules by wound fibroblasts, accelerating development of granulation tissue." BMC Cell Biology 3 (2002).
Source
scival
Published In
BMC Cell Biology
Volume
3
Publish Date
2002
DOI
10.1186/1471-2121-3-13

Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression.

Thrombin is primarily known for its role in homeostasis and thrombosis. However, this enzyme also plays important roles in wound healing and pathologic situations such as inflammation and tumorigenesis. Among the molecules stimulated by thrombin in these latter processes are the stress response proteins, chemokines. Chemokines are also known for their roles in inflammatory responses and tumor development. These correlative observations strongly suggest that chemokines may be mediators of some of thrombin's functions in these processes. Elucidation of the molecular mechanisms of stimulation of chemokines by thrombin may help to unravel the ways in which their expression can be modulated. Up-regulation of the chemokine 9E3/cCAF by thrombin occurs via its proteolytically activated receptor with subsequent transactivation of the epidermal growth factor receptor tyrosine kinase. This study shows that stimulation by thrombin very rapidly activates this chemokine at the transcriptional level, that 2 Elk1 binding elements located between -534 and -483 bp of the promoter are major thrombin response elements, that activation occurs via the Elk1 transcription factor, and that the latter is directly activated by MEK1/ERK2. The common occurrence of Elk1 binding domains in the promoters of immediate early response genes suggests that it may be characteristically involved in gene activation by stress-inducing agents. (Blood. 2000;96:3696-3706)

Authors
Li, QJ; Vaingankar, S; Sladek, FM; Martins-Green, M
MLA Citation
Li, QJ, Vaingankar, S, Sladek, FM, and Martins-Green, M. "Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression." Blood 96.12 (December 1, 2000): 3696-3706.
PMID
11090049
Source
pubmed
Published In
Blood
Volume
96
Issue
12
Publish Date
2000
Start Page
3696
End Page
3706

Isolation and characterization of a new chemokine receptor gene, the putative chicken CXCR1.

This study delineates the isolation and characterization of a novel chemokine receptor gene, the putative chicken CXC receptor 1 (cCXCR1). Using a human CXCR1 probe, we isolated several positive clones from a chicken genomic library. One of the clones contained a fragment of approximately 5000bp that hybridized strongly with the hCXCR1 probe. This fragment was sequenced and subjected to a variety of computer analyses. The open reading frame for this gene predicts a seven transmembrane domain protein with all the characteristics of a chemokine receptor and with 67% sequence homology to hCXCR1, 65% to hCXCR2 and also with considerable sequence homology to other human chemokine receptors such as hCXCR4 (50%), hCCR2 (49%) and hCCR1 (49%). However, the homology to a previously isolated potential G-protein-coupled receptor for chickens (AvCRL1) is only 47%. Using 5' RACE, two transcription initiation sites were identified suggesting the potential for the expression of two protein isoforms (I and II) in vivo. The promoter for the putative cCXCR1 contains a variety of consensus transcription factor binding elements that can potentially be involved in the expression of this chicken receptor upon stimulation by stress-inducing agents. RT-PCR analysis was used to determine the pattern of expression of the larger isoform (I) of this receptor in a variety of tissues. This form of the receptor is expressed primarily in the organs of the gastrointestinal tract, tissues that are frequently exposed to stress-inducing agents, but not in the central nervous system, tissues that are protected from insult by the blood barrier. Using the same RT-PCR approach we show that stress-inducing agents, such as 'first-hand' and 'second-hand' cigarette smoke components, tumor promoters and thrombin, differentially stimulate the expression of the isoform I in primary fibroblasts. Thrombin is an enzyme that plays many important roles in thrombosis, angiogenesis and wound healing and exposure to both cigarette smokes and/or to tumor promoters can lead to tumorigenesis. Therefore, upregulation of chemokines and their receptors by stress-inducing agents can confer highly regulated modulation of cellular responses to traumatic and pathological situations.

Authors
Li, QJ; Lu, S; Ye, RD; Martins-Green, M
MLA Citation
Li, QJ, Lu, S, Ye, RD, and Martins-Green, M. "Isolation and characterization of a new chemokine receptor gene, the putative chicken CXCR1." Gene 257.2 (October 31, 2000): 307-317.
PMID
11080597
Source
pubmed
Published In
Gene
Volume
257
Issue
2
Publish Date
2000
Start Page
307
End Page
317

Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiple signal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor.

Using primary fibroblasts in culture, we have investigated the signal transduction mechanisms by which phorbol esters, a class of tumor promoters, activate the 9E3 gene and its chemokine product the chicken chemotactic and angiogenic factor. This gene is highly stimulated by phorbol 12,13-dibutyrate (PDBu) via three pathways: (i) a small contribution through protein kinase C (the commonly recognized pathway for these tumor promoters), (ii) a contribution involving tyrosine kinases, and (iii) a larger contribution via pathways that can be interrupted by dexamethasone. All three of these pathways converge into the mitogen-activated protein kinases, MEK1/ERK2. Using a luciferase reporter system, we show that although both the AP-1 and PDRIIkB (a NFkappaB-like factor in chickens) response elements are capable of activation in these normal cells, regions of the 9E3 promoter containing them are unresponsive to PDBu stimulation. In contrast, we show for the first time that activation by PDBu occurs through a segment of the promoter containing Elk1 response elements; deletion and mutation of these elements abrogates 9E3/chicken chemotactic and angiogenic factor expression. Electrophoretic mobility shift assays and functional studies using PathDetect systems show that stimulation of the cells by phorbol esters leads to activation of the Elk1 transcription factor, which binds to its element in the 9E3 promoter.

Authors
Li, Q; Vaingankar, SM; Green, HM; Martins-Green, M
MLA Citation
Li, Q, Vaingankar, SM, Green, HM, and Martins-Green, M. "Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiple signal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor." J Biol Chem 274.22 (May 28, 1999): 15454-15465.
PMID
10336436
Source
pubmed
Published In
The Journal of biological chemistry
Volume
274
Issue
22
Publish Date
1999
Start Page
15454
End Page
15465

Management of residual cancer tissue on cutting surface with ethanal during hepatectomy

Due to the fact that primary liver cancer possesses no capsule in addition to many of the following features such as infiltrative growth, ill-defined border, associated with liver cirrhosis, cutting surface with residue of carcinoma during hepatectomy is very common which leads to high recurrence rate. From January 1990 through December 1993, 81 cases of primary liver cancer which had residual cancer tissue at the cutting surface during hepatectomy were treated with ethanal application. The 1-, 2-, 3-year-survival rate were 93.8%, 81.2% and 56.1% respectively for the 45 patients who had only apparent residual carcinoma at the cutting surface, while the same rates were 54.1%, 29.6%, 11.9% for the other 36 patients who had both involved nodes carcinoma on the cutting surface. The results showed that local application of ethanol for cancer tissue on the cutting surface during hepatectomy is a useful and simple means to improve the prognosis.

Authors
Li, JQ; Zhang, YQ; Yuan, YF
MLA Citation
Li, JQ, Zhang, YQ, and Yuan, YF. "Management of residual cancer tissue on cutting surface with ethanal during hepatectomy." Chinese Journal of Clinical Oncology 22.10 (January 1, 1995): 716-717.
Source
scopus
Published In
Chinese Journal of Clinical Oncology
Volume
22
Issue
10
Publish Date
1995
Start Page
716
End Page
717

Biological function and mechanism of miR-33a in prostate cancer survival and metastasis: via downregulating Engrailed-2

Authors
Li, Q; Lu, S; Li, X; Hou, G; Yan, L; Zhang, W; Qiao, B
MLA Citation
Li, Q, Lu, S, Li, X, Hou, G, Yan, L, Zhang, W, and Qiao, B. "Biological function and mechanism of miR-33a in prostate cancer survival and metastasis: via downregulating Engrailed-2 (Published online)." Clinical and Translational Oncology.
Source
crossref
Published In
Clinical and Translational Oncology
DOI
10.1007/s12094-016-1564-3
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