Ontogeny of natural regulatory T cells.

描述(申请人提供)：T细胞上的抗原受体(TCRs)是由TCRs和MHC分子之间的相互作用形成的，MHC分子与自身和非自身来源的多肽结合。在胸腺中，这些相互作用促进T细胞与对自身MHC/肽复合体具有低/中亲和力的TCR分化。然而，仅具有低/中亲和力的TCR才能促进T细胞分化的教条受到了挑战，因为有报道表明，CD4+调节细胞通常表达高亲和力的自身反应性TCR。调节性CD4+细胞上TCR的这一独特功能将指导这些细胞在胸腺中的谱系承诺，并启动特定转录因子Foxp3的表达。在这里，我们想要检查自身反应性TCR是否是调节性T细胞成熟和抑制功能所必需的。由于T细胞上TCRs的自然多样性是巨大的，我们制造了T细胞被限制表达TCRs的微型谱系的小鼠(TCRmini小鼠)。在这个模型中，可以全面监测单个T细胞在胸腺和外周发育过程中的情况。在TCRmini小鼠中，CD4+T细胞以幼稚和调节性的方式自然成熟，我们进一步将这些小鼠与在Foxp3调控序列下表达GFP报告基因的小鼠杂交。使用这些不同品系的TCRmini小鼠，我们将检测在胸腺中由AIRE转录因子控制的组织特异性多肽是否参与了CD4+Foxp3-髓质胸腺细胞向CD4+Foxp3+谱系的转化。这些实验将使用TCRmini AIRE+和AIRE-小鼠进行。我们还旨在探讨胸腺中同源抗原存在与CD4+Foxp3+T细胞分化的生理学相关性。我们相信，这些研究将揭示TCR/MHC/多肽相互作用如何在体内控制Foxp3+调节性T细胞的功能和命运。公共卫生相关性：这项建议侧重于研究T淋巴细胞成熟的机制，T淋巴细胞自然具有抑制和调节功能。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是如何分化的，对于开发治疗自身免疫性、感染性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.