Apoptosis is an essential physiological process required for the development and maintenance of homeostasis in an organism. The Bcl-2 proto-oncogene is a critical regulator of the apoptotic signaling pathways. Altered expression of Bcl-2 contributes to cancer pathogenesis and resistance to chemotherapeutic drugs due to failed induction of apoptosis. Apoptosis serves to eliminate majority of the developing thymocytes that are either not recognized by major histocompatibility complexes or self-reactive. By gene targeting, we have demonstrated that retinoid-related orphan receptor gamma (RORgamma), a member of the nuclear receptor family, plays a critical role in the development of thymocytes and lymph nodes. In the absence of RORgamma, thymocytes undergo rapid apoptosis and unregulated entry into S phase of the cell cycle. Correspondingly, RORgamma deficient thymocytes have significant lower levels of anti-apoptotic Bcl-xL and cell cycle inhibitor p27kip1. Overexpression of Bcl-xL in the RORgamma deficient thymocytes restores survival and cell cycle progression. RORgamma null mice fail to develop lymph nodes, likely due to absence of lymph node progenitors in the early embryonic stages. We hypothesize that RORgamma regulates expression of the critical survival and cell cycle molecules that are required for the development of thymocytes and lymph nodes. We propose to study the molecular mechanisms responsible for RORgamma mediated transcription and its function in thymocyte maturation in vivo. In addition, we will examine how RORgamma regulates the development of peripheral lymphoid organs. The proposed studies will gain insight into nuclear receptor regulated functions in development of T cells and the secondary lymphoid tissues in vivo.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunobiology Study Section (IMB)
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Prabhudas, Mercy R
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University of Illinois at Chicago
Schools of Medicine
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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; 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; 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; 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

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