Ontogeny of natural regulatory T cells.

描述（由申请人提供）：T细胞上的抗原受体（TCR）库由TCR和与自身和非自身来源的肽结合的MHC分子之间的相互作用形成。在胸腺中，这些相互作用促进具有对自身MHC/肽复合物具有低/中等亲和力的TCR的T细胞的分化。然而，只有对自身促进T细胞分化具有低/中等亲和力的TCR的教条已经受到证明CD 4+调节细胞经常表达高亲和力、自身反应性TCR的报道的挑战。TCR在调节性CD 4+细胞上的这种独特特征将指导这些细胞在胸腺中的谱系定型并启动特异性转录因子Foxp 3的表达。在这里，我们想检查自身反应性TCR是否是调节性T细胞成熟和抑制功能的必需品。由于T细胞上TCR的天然多样性是巨大的，我们已经制备了其中T细胞被限制表达TCR的微型库的小鼠（TCRmini小鼠）。在该模型中，可以在胸腺中以及随后在外周中发育的过程中全面监测单个T细胞。在TCRmini小鼠中，CD 4 + T细胞自然成熟为幼稚和调节性的，并且我们进一步将这些小鼠与在Foxp 3调节序列下表达GFP报告基因的小鼠杂交。使用这些不同品系的TCRmini小鼠，我们将检查组织特异性肽（其在胸腺中的表达由AIRE转录因子控制）是否参与CD 4 + Foxp 3-髓质胸腺细胞向CD 4 + Foxp 3+谱系的转化。这些实验将使用TCRmini AIRE+和AIRE-小鼠进行。我们还旨在研究胸腺中同源抗原的存在对CD 4 + Foxp 3 + T细胞分化的生理相关性。我们相信这些研究将揭示TCR/MHC/肽相互作用如何在体内支配Foxp 3+调节性T细胞的功能和普罗维登斯。公共卫生相关性：该建议的重点是研究自然具有抑制和调节功能的T淋巴细胞的成熟机制。这些调节性T淋巴细胞监督其他免疫细胞的功能。更好地了解这些细胞如何分化对于开发治疗自身免疫性疾病、感染性疾病和肿瘤性疾病的新策略至关重要。

DESCRIPTION (provided by applicant): Repertoire of antigen receptors (TCRs) on T cells is shaped by interactions between TCRs and MHC molecules bound with peptides of self and non-self origin. In thymus, these interactions promote differentiation of T cells with TCRs with low/intermediate affinity for self-MHC/peptide complexes. However, the dogma that only TCRs with low/intermediate affinity for self promote T cell differentiation has been challenged by the reports demonstrating that CD4+ regulatory cells often express high affinity, autoreactive TCRs. This unique feature of TCRs on regulatory CD4+ cells would direct these cells lineage commitment in the thymus and initiate expression of specific transcription factor Foxp3. Here we would like to examine if autoreactive TCRs are obligatory for regulatory T cells maturation and suppressive functions. Because natural diversity of TCRs on T cells is enormous, we have made mice where T cells are constrained to express the mini-repertoire of TCRs (TCRmini mice). In this model, individual T cells can be comprehensively monitored during their development in the thymus and later in the periphery. In TCRmini mice CD4+ T cells naturally mature as naive and regulatory and we further crossed these mice with mice expressing GFP reporter gene under Foxp3 regulatory sequences. Using these different strains of TCRmini mice we will examine if tissue specific peptides, which expression in the thymus is controlled by AIRE transcription factor, participate in conversion of CD4+Foxp3- medullary thymocytes to CD4+Foxp3+ lineage. These experiments will be performed using TCRmini AIRE+ and AIRE- mice. We also purpose to investigate the physiological relevance of presence of cognate antigen in the thymus on the differentiation of CD4+Foxp3+ T cells. We believe that these studies will reveal how TCR/MHC/peptide interactions govern the function and providence of Foxp3+ regulatory T cells in vivo. PUBLIC HEALTH RELEVANCE: This proposal focuses on investigating the mechanisms of maturation of T lymphocytes that naturally have suppressive and regulatory function. These regulatory T lymphocytes supervise the function of other immune cells. Better understanding how these cells differentiate is critical for the development of new strategies to treat autoimmune, infectious and neoplastic diseases.