Abstract

Generation of robust Th17 immune responses required for clearance of certain pathogens depends on promoting Th17 while reciprocally inhibiting Treg formation. Whereas, effective prevention of Th17-mediated autoimmunity such as EAE depends on inhibiting pathogenic Th17 while reciprocally promoting Treg formation. However, little is known about the mechanisms responsible for coordination of Th17 and Treg differentiation. Our preliminary results demonstrated that PKC-theta is a critical checkpoint for reciprocal Th17 and Treg differentiation. The proposed studies will investigate the function of PKC- theta and RORyt in the reciprocal Th17 and iTreg differentiation. Based on the knowledge learned from the studies, we expect to develop PKC-8-based treatments for prevention of EAE, an animal model of multiple sclerosis. It is expected that such treatments will have a broader applicability in the prevention of Th17-mediated autoimmunity. In addition, the proposed research has significance to basic T cell biology, as it is expected to reveal novel molecular mechanisms for PKC- theta -mediated TCR signals in the coordination of Th17 and iTreg differentiation.

Public Health Relevance

This proposal is to study the mechanisms responsible for PKC-theta and RORgamma T- regulated Th17 and Treg differentiation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI053147-08
Application #
8196909
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2002-12-01
Project End
2015-10-31
Budget Start
2011-11-01
Budget End
2012-10-31
Support Year
8
Fiscal Year
2012
Total Cost
$415,000
Indirect Cost
$165,000

  Institution

Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010

  Publications

Sen, Subha; He, Zhiheng; Ghosh, Shubhamoy et al. (2018) PRMT1 Plays a Critical Role in Th17 Differentiation by Regulating Reciprocal Recruitment of STAT3 and STAT5. J Immunol 201:440-450
Zhang, Jing; He, Zhiheng; Sen, Subha et al. (2018) TCF-1 Inhibits IL-17 Gene Expression To Restrain Th17 Immunity in a Stage-Specific Manner. J Immunol 200:3397-3406
Sen, Subha; Wang, Fei; Zhang, Jing et al. (2018) SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate ROR?t activity in a PKC-?-dependent manner. Proc Natl Acad Sci U S A 115:E458-E467
He, Zhiheng; Wang, Fei; Zhang, Jing et al. (2017) Regulation of Th17 Differentiation by IKK?-Dependent and -Independent Phosphorylation of ROR?t. J Immunol 199:955-964
He, Zhiheng; Ma, Jian; Wang, Ruiqing et al. (2017) A two-amino-acid substitution in the transcription factor ROR?t disrupts its function in TH17 differentiation but not in thymocyte development. Nat Immunol 18:1128-1138
He, Zhiheng; Wang, Fei; Ma, Jian et al. (2016) Ubiquitination of ROR?t at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment. J Immunol 197:1148-58
Ma, Jian; Wang, Ruiqing; Fang, Xianfeng et al. (2012) ?-catenin/TCF-1 pathway in T cell development and differentiation. J Neuroimmune Pharmacol 7:750-62
Kwon, Myung-Ja; Ma, Jian; Ding, Yan et al. (2012) Protein kinase C-? promotes Th17 differentiation via upregulation of Stat3. J Immunol 188:5887-97
Sun, Zuoming (2012) Intervention of PKC-? as an immunosuppressive regimen. Front Immunol 3:225
Ma, Jian; Ding, Yan; Fang, Xianfeng et al. (2012) Protein kinase C-? inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. J Immunol 188:5337-47

Showing the most recent 10 out of 26 publications