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

描述(申请人提供)：功能性适应性免疫系统依赖于T淋巴细胞的多样性和自我耐受性，这些T淋巴细胞在胸腺中产生并维持在外周淋巴器官中。近年来的研究认为，细胞因子转化生长因子-β是胸腺T细胞发育的重要调节因子，也是免疫应答过程中外周T细胞稳态、自身抗原耐受和T细胞分化的重要调节因子。这项建议的长期目标是阐明转化生长因子-β调节T细胞的机制。在T细胞特异性缺失TGFBR2基因的小鼠中观察到的T细胞缺陷与常见的伽玛链受体家族的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CD127(IL-7受体阿尔法链)在转化生长因子-β受体II缺陷的胸腺细胞和幼稚T细胞中的表达功能，将使用一株CD127转基因小鼠。为了确定CD122(IL-2/15受体β链)异常表达在转化生长因子-β受体II缺陷效应T细胞中的作用，我们将利用一株IL-15缺陷小鼠。这些小鼠将与T细胞特异性转化生长因子-β受体II缺陷小鼠杂交，T细胞缺陷的纠正将被确定。转化生长因子-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Eome的异常表达有关。GFI-1、T-bet和eome在控制CD127和CD122表达以及转化生长因子-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来解决。最后，将研究转化生长因子-β激活的Smad蛋白在GFI-1、T-bet和T细胞中Eome抑制中的作用。这项提案中概述的项目的成功完成将产生对转化生长因子-β和T细胞调节中常见的伽马链细胞因子之间的相互作用的机械性见解。 公共卫生相关性：T淋巴细胞在免疫相关疾病中发挥关键作用，如感染、自身免疫性疾病、移植排斥反应和癌症。现已证实，分泌分子转化生长因子-β是T细胞分化和功能的关键调节因子。这里提出的实验将定义转化生长因子-β如何控制T细胞。

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.