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

T 细胞调节中的 TGF-β 和常见伽马链细胞因子串扰

• 批准号: 7893474
• 负责人: Ming Li
• 金额: $ 42.75万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893474
• 关键词: Address; Autoantigens; Autoimmune Diseases; Binding; Cytokine Receptors; Cytokine Signaling; Defect; Development; Disease; Family; Genes; Graft Rejection; Homeostasis; IL2RB gene; IL7R gene; Immune; Immune response; Immune system; Infection; Interleukin 2 Receptor Gamma; Interleukin 7 Receptor; Interleukin-15; Interleukin-2; Interleukin-7; Lymphoid; Maintenance; Malignant Neoplasms; Molecular; Mus; Organ; Peripheral; Play; Population; Regulation; Repression; Role; Signal Pathway; Signal Transduction; Smad Proteins; Smad protein; T cell differentiation; T cell regulation; T cell response; T-Cell Development; T-Lymphocyte; Thymus Gland; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Transgenic Mice; Work; alpha chain interleukin-7 receptor; cytokine; insight; public health relevance; receptor; receptor expression; research study; thymocyte; transcription factor

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.

描述（由申请人提供）：功能自适应免疫系统取决于在胸腺中产生并维持在外周淋巴器官中生成的T淋巴细胞的多样化和自耐受群体。最近的研究定义了细胞因子转化生长因子β（TGF-β）是胸腺T细胞发育的关键调节剂，以及在免疫反应过程中外周T细胞稳态，对自我抗原的耐受性和T细胞分化的关键参与者。该建议的长期目标是阐明TGF-β调节T细胞的机制。 T细胞特异性缺失TGFBR2基因的T细胞缺陷与普通γ-链受体家族的细胞因子的受体异常表达有关，包括脑膜间7（IL-7），IL-2），IL-2和IL-15。为了确定TGF-β受体II缺陷胸腺细胞和幼稚T细胞中受损的CD127（IL-7受体α链）表达的功能，将使用CD127转基因小鼠的菌株。为了确定异常CD122（IL-2/15受体β链）在TGF-β受体II缺陷效应T细胞中的表达，将利用IL-15缺陷型小鼠的菌株。这些小鼠将与T细胞特异性TGF-β受体II缺陷型小鼠交叉，并确定T细胞缺陷的校正。 TGF-β受体II缺陷型T细胞的缺陷与GFI-1，T-BET和EOME的异常表达相关，这是调节CD127和CD122表达的转录因子。 GFI-1，T-BET和EOMES在控制CD127和CD122表达以及TGF-β受体II缺陷T细胞活性中的功能将使用这些转录因子缺乏的小鼠来解决。最后，将研究TGF-β激活的SMAD蛋白在T细胞中GFI-1，T-BET和EOMES抑制中的作用。在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-beta和常见的γ链细胞因子之间串扰的机械见解。 公共卫生相关性：T淋巴细胞在免疫相关疾病（例如感染，自身免疫性疾病，移植排斥和癌症）中起关键作用。已经确定分泌的分子TGF-β是T细胞分化和功能的关键调节剂。这里提出的实验将定义TGF-beta如何控制T细胞。