To become competent effector Th17 cells mediating the actual immune responses, T cells have to undergo two ROR?t-dependent differentiation processes sequentially carried out in thymus and peripheral lymphoid tissues. ROR?t is up-regulated in thymocyes to enhance the survival required for completion of T cell maturation process in thymus, and absence of ROR?t activity severely impairs thymocyte development that eventually leads to lymphoma. ROR?t is again up-regulated in peripheral CD4+ T cells to instruct the differentiation of Th17 cells that mediate many types of autoimmunity. ROR?t is thus considered an important drug target for treatment of Th17-dependent autoimmunity. However, little is known about the common and distinct mechanisms that ROR?t utilize to regulate these two differentiation processes. Our goal is to understand the function of ROR?t in both thymocytes and Th17 cells, which will facilitate to develop drugs specifically targeting Th17-dependent autoimmunity, but not interfering with thymocyte development that leads to lymphoma. The objective of this application is to understand how both thymocytes and peripheral T cells differentially use the same transcription factor ROR?t to regulate their differentiation processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI109644-02
Application #
8810643
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Prabhudas, Mercy R
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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He, Zhiheng; Zhang, Jing; Du, Qian et al. (2018) SRC3 Is a Cofactor for ROR?t in Th17 Differentiation but Not Thymocyte Development. J Immunol :
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
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