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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI053147-09
Application #
8369863
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
2012-11-01
Budget End
2013-10-31
Support Year
9
Fiscal Year
2013
Total Cost
$390,100
Indirect Cost
$155,100
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
He, Zhiheng; Wang, Fei; Ma, Jian et al. (2016) Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment. J Immunol 197:1148-58
Kwon, Myung-Ja; Ma, Jian; Ding, Yan et al. (2012) Protein kinase C-ýý promotes Th17 differentiation via upregulation of Stat3. J Immunol 188:5887-97
Ma, Jian; Wang, Ruiqing; Fang, Xianfeng et al. (2012) β-catenin/TCF-1 pathway in T cell development and differentiation. J Neuroimmune Pharmacol 7:750-62
Sun, Zuoming (2012) Intervention of PKC-θ as an immunosuppressive regimen. Front Immunol 3:225
Ma, Jian; Ding, Yan; Fang, Xianfeng et al. (2012) Protein kinase C-ýý inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. J Immunol 188:5337-47
Fang, Xianfeng; Wang, Ruiqing; Ma, Jian et al. (2012) Ameliorated ConA-induced hepatitis in the absence of PKC-theta. PLoS One 7:e31174
Wang, Ruiqing; Xie, Huimin; Huang, Zhaofeng et al. (2011) Transcription factor network regulating CD(+)CD8(+) thymocyte survival. Crit Rev Immunol 31:447-58
Ma, Jian; Wang, Ruiqing; Fang, Xianfeng et al. (2011) Critical role of TCF-1 in repression of the IL-17 gene. PLoS One 6:e24768
Wang, Ruiqing; Xie, Huimin; Huang, Zhaofeng et al. (2011) T cell factor 1 regulates thymocyte survival via a RORγt-dependent pathway. J Immunol 187:5964-73
Kwon, Myung-Ja; Wang, Ruiqing; Ma, Jian et al. (2010) PKC-θ is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection. Endocr Metab Immune Disord Drug Targets 10:367-72

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