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

描述（由申请方提供）：功能性适应性免疫系统依赖于在胸腺中产生并在外周淋巴器官中维持的多样化和自我耐受的T淋巴细胞群。最近的研究已经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，以及在免疫应答期间外周T细胞稳态、对自身抗原的耐受性和T细胞分化中的关键作用者。该提案的长期目标是阐明TGF-β调节T细胞的机制。在具有Tgfbr 2基因的T细胞特异性缺失的小鼠中观察到的T细胞缺陷与常见γ链受体家族的细胞因子（包括白介素7（IL-7）、IL-2和IL-15）的受体的异常表达相关。为了确定TGF-β受体II缺陷型胸腺细胞和初始T细胞中受损的CD 127（IL-7受体α链）表达的功能，将使用一种CD 127转基因小鼠品系。为了确定TGF-β受体II缺陷型效应T细胞中异常CD 122（IL-2/15受体β链）表达的作用，将使用IL-15缺陷型小鼠品系。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细胞缺陷的校正。TGF-β受体II缺陷型T细胞的缺陷还与Gfi-1、T-bet和Eomes的异常表达相关，这些转录因子调节CD 127和CD 122的表达。Gfi-1、T-bet和Eomes在控制CD 127和CD 122表达和TGF-β受体II缺陷型T细胞活性中的功能将使用这些转录因子缺陷的小鼠来解决。最后，将研究TGF-β激活的Smad蛋白在T细胞中Gfi-1、T-bet和Eomes阻遏中的作用。本提案中概述的项目的成功完成将产生对TGF-β和T细胞调节中常见的γ链细胞因子之间的串扰的机械见解。

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.