A functional adaptive immune system depends on a diverse and self-tolerant population of T lymphocytes that are generated in the thymus and maintained in the peripheral lymphoid organs. Recent studies have defined the cytokine transforming growth factor-beta (TGF-beta) as a critical regulator of thymic T cell development as well as a crucial player in peripheral T cell homeostasis, tolerance to self-antigens, and T cell differentiation during the immune responses. The long-term objective of this proposal is to elucidate the mechanisms by which TGF-beta regulates T cells. T cell defects observed in mice with T cell-specific deletion of Tgfbr2 gene are associated with abnormal expression of receptors for cytokines of the common gamma-chain receptor family including interleukin 7 (IL-7), IL-2, and IL-15. To determine the function of compromised CD127 (IL-7 receptor alpha chain) expression in TGF-beta receptor II-deficient thymocytes and naive T cells, a strain of CD127 transgenic mice will be used. To determine the role of anomalous CD122 (IL-2/15 receptor beta chain) expression in TGF-beta receptor II-deficient effector T cells, a strain of IL-15-deficient mice will be utilized. These mice will be crossed with T cell-specific TGF-beta receptor II-deficient mice, and the correction of T cell defects will be determined. Defects of TGF-beta receptor II-deficient T cells are additionally associated with abnormal expression of Gfi-1, T-bet, and Eomes, transcription factors that regulate CD127 and CD122 expression. The functions of Gfi-1, T-bet, and Eomes in control of CD127 and CD122 expression and TGF- beta receptor II-deficient T cell activity will be addressed using mice that are deficient in these transcription factors. Finally, the role of TGF-beta-activated Smad proteins in Gfi-1, T-bet, and Eomes repression in T cells will be studied. Successful completion of the projects outlined in this proposal will generate mechanistic insights into the crosstalk between TGF-beta and the common gamma-chain cytokines in T cell regulation.

Public Health Relevance

T lymphocytes play a key role in immune-related diseases such as infection, autoimmune diseases, transplant rejection, and cancer. It has been established that the secreted molecule TGF-beta is a critical regulator of T cell differentiation and function. Experiments proposed here will define how TGF-beta controls T cells.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Ouyang, Weiming; Oh, Soyoung A; Ma, Qian et al. (2013) TGF-* cytokine signaling promotes CD8+ T cell development and low-affinity CD4+ T cell homeostasis by regulation of interleukin-7 receptor * expression. Immunity 39:335-46
Ouyang, Weiming; Li, Ming O (2011) Foxo: in command of T lymphocyte homeostasis and tolerance. Trends Immunol 32:26-33
Donkor, Moses K; Sarkar, Abira; Savage, Peter A et al. (2011) T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-?1 cytokine. Immunity 35:123-34
Gutcher, Ilona; Donkor, Moses K; Ma, Qian et al. (2011) Autocrine transforming growth factor-?1 promotes in vivo Th17 cell differentiation. Immunity 34:396-408
Chen, Yi; Haines, Christopher J; Gutcher, Ilona et al. (2011) Foxp3(+) regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity 34:409-21