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.
This proposal is to study the mechanisms responsible for PKC-theta and RORgamma T- regulated Th17 and Treg differentiation.
|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) T cell factor 1 regulates thymocyte survival via a ROR?t-dependent pathway. J Immunol 187:5964-73|
|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|
|Manicassamy, Santhakumar; Yin, Dengping; Zhang, Zheng et al. (2008) A critical role for protein kinase C-theta-mediated T cell survival in cardiac allograft rejection. J Immunol 181:513-20|
|Gupta, Sonal; Manicassamy, Santhakumar; Vasu, Chenthamarakshan et al. (2008) Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol Immunol 46:213-24|
|Manicassamy, Santhakumar; Gupta, Sonal; Huang, Zhaofeng et al. (2008) Requirement of calcineurin a beta for the survival of naive T cells. J Immunol 180:106-12|
|Huang, Zhaofeng; Wang, Ruiqing; Xie, Huimin et al. (2008) Stabilized beta-catenin potentiates Fas-mediated T cell apoptosis. J Immunol 180:6586-92|
|Manicassamy, Santhakumar; Sun, Zuoming (2007) The critical role of protein kinase C-theta in Fas/Fas ligand-mediated apoptosis. J Immunol 178:312-9|
|Huang, Zhaofeng; Xie, Huimin; Wang, Ruiqing et al. (2007) Retinoid-related orphan receptor gamma t is a potential therapeutic target for controlling inflammatory autoimmunity. Expert Opin Ther Targets 11:737-43|
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