TGF-beta and Common gamma-Chain Cytokine Crosstalk in T Cell Regulation

描述（由申请人提供）：功能性适应性免疫系统依赖于胸腺中产生并在外周血淋巴器官中维持的多样化和自我耐受的T淋巴细胞群。最近的研究将细胞因子转化生长因子- β (tgf - β)定义为胸腺T细胞发育的关键调节因子，以及免疫应答过程中外周T细胞稳态、对自身抗原的耐受性和T细胞分化的关键参与者。这项建议的长期目标是阐明tgf - β调节T细胞的机制。Tgfbr2基因在T细胞特异性缺失小鼠中观察到的T细胞缺陷与常见γ链受体家族细胞因子受体的异常表达有关，包括白细胞介素7 （IL-7）、IL-2和IL-15。为了确定tgf - β受体ii缺陷胸腺细胞和幼稚T细胞中CD127 （IL-7受体α链）表达受损的功能，将使用一株CD127转基因小鼠。为了确定CD122 （IL-2/15受体β链）异常表达在tgf - β受体ii缺陷效应T细胞中的作用，将利用一株il -15缺陷小鼠。这些小鼠将与T细胞特异性tgf - β受体ii缺陷小鼠杂交，并确定T细胞缺陷的纠正。tgf - β受体ii缺陷T细胞的缺陷还与调节CD127和CD122表达的转录因子Gfi-1、T-bet和Eomes的异常表达有关。Gfi-1、T-bet和Eomes在控制CD127和CD122表达以及TGF- β受体ii缺陷T细胞活性方面的功能将通过缺乏这些转录因子的小鼠进行研究。最后，将研究tgf - β激活的Smad蛋白在T细胞中Gfi-1、T-bet和Eomes抑制中的作用。本提案中概述的项目的成功完成将产生对T细胞调节中tgf - β和常见γ链细胞因子之间串扰的机制见解。

DESCRIPTION (provided by applicant): 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.