In human, uncontrolled pathogenic responses of IL-17+ cells are linked to various autoimmunity such as multiple sclerosis, Colitis and even autism whereas defective IL-17+ cells impairs protective immunity against infection by bacteria and fungus. IL-17 is produced from both adaptive Th17 cells and innate lymphocytes that contribute to immune responses at different phases. Effective control of the scale of Th17 responses is thus critical for treatment of above immune dysfunction. SRC1 and SRC3 are the functional co-factors for ROR?t, the essential transcription factor controlling Th17 function. Currently, poor understanding of the mechanisms responsible for the function of these co-factors prevents the development of potent clinical treatments to boost protective Th17 immunity against infection and repress pathogenic immunity responsible for autoimmunity. The objective of this proposal is to determine the role of SRC1 and SRC3 in the regulation of T cell-mediated immunity. Our proposed study will lay the foundation for understanding the fundamental role of SRC1 and SRC3 in adaptive T cells and innate lymphocytes, which will facilitate the development of specific and effective immunomodulatory therapies to boost protective immunity and suppress pathogenic IL-17+ cell- mediated autoimmunity.

Public Health Relevance

This project is to understand the function of nuclear receptor co-activators, SRC1 and SRC3 in T cells. This study will facilitate the development of effective immunotherapies to boost protective Th17 immune responses against pathogens while impairing the pathogenic Th17 responses that cause autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI109644-07
Application #
9858214
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Kelly, Halonna R
Project Start
2014-05-01
Project End
2024-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
7
Fiscal Year
2020
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
He, Zhiheng; Zhang, Jing; Huang, Zhaofeng et al. (2018) Sumoylation of ROR?t regulates TH17 differentiation and thymocyte development. Nat Commun 9:4870
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
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
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