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.
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.
|Sanjabi, Shomyseh; Oh, Soyoung A; Li, Ming O (2017) Regulation of the Immune Response by TGF-?: From Conception to Autoimmunity and Infection. Cold Spring Harb Perspect Biol 9:|
|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|
|Oh, Soyoung A; Li, Ming O (2013) TGF-?: guardian of T cell function. J Immunol 191:3973-9|
|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|
|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|
|Ouyang, Weiming; Li, Ming O (2011) Foxo: in command of T lymphocyte homeostasis and tolerance. Trends Immunol 32:26-33|
|Sarkar, Abira; Donkor, Moses K; Li, Ming O (2011) T cell- but not tumor cell-produced TGF-?1 promotes the development of spontaneous mammary cancer. Oncotarget 2:1339-51|
|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|
|Ouyang, Weiming; Beckett, Omar; Ma, Qian et al. (2010) Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32:642-53|
|Di Santo, James P (2010) Immunology. A guardian of T cell fate. Science 329:44-5|