SELF PEPTIDES BOUND TO MHC CLASS II IN T CELL SELECTION

描述（由申请方提供）：尽管对胸腺中经过阳性和阴性选择的胸腺细胞进行了严格的质量控制，但仍有大量自身反应性T细胞逃逸至外周。CD 25 + CD 4调节性T细胞（Treg）在预防自身免疫中起关键作用。最近观察到共表达转基因TCR及其同源抗原的小鼠中Treg数量显著增加，这表明这些细胞对自身II类结合肽的亲和力增加。然而，在天然产生的Treg中表达的TCR的肽特异性，以及在Treg分化的不同阶段识别特异性自身肽的要求仍然是本领域的主要未知数。这种知识的缺乏阻碍了我们对这一关键T细胞亚群的发育和功能的进一步了解。我们的初步研究表明，Treg的相当大的比例是特异性的普遍表达的II类结合肽存在于高拷贝数。基于这些数据和我们最近观察到的MHC II类依赖性增殖的Treg在淋巴细胞减少的主机，我们进一步假设，Treg TCR与MHC-肽配体的相互作用所需的外周维持的Treg子集及其功能。在这项提案中，我们将测试这些假设的特点调节性T细胞特异性，并通过进一步调查的要求自我肽识别调节性T细胞的发展在胸腺和他们的功能在周边。在前面的实验中，我们将尝试直接鉴定由Treg TCR识别的肽-MHC II类复合物。在后面的研究中，我们将使用在“单肽”小鼠和具有II类结合自身肽野生型库的小鼠中选择的转基因Treg TCR，以及来自“单肽”小鼠的多克隆Treg。这些研究将提供Treg识别特定MHC II类结合肽在Treg胸腺发育、外周维持和Treg介导的自身免疫保护中的作用的新信息。这些知识对于理解Treg生物学和开发Treg细胞疗法以减轻自身免疫和移植排斥具有重要意义。

DESCRIPTION (provided by applicant): Despite strict quality control of thymocytes subjected to positive and negative selection in the thymus, a number of autoreactive T cells escape into the periphery. CD25+CD4 regulatory T cells (Treg) play a key role in prevention of autoimmunity. Recent observations of significantly increased Treg numbers in mice coexpressing a transgenic TCR and its cognate antigen suggested that these cells have increased affinity for self class II-bound peptides. However, peptide specificity of TCR expressed in naturally arising Treg, and requirements for the recognition of specific self-peptides at different stages of Treg differentiation remain a major unknown in the field. This lack of knowledge impedes further progress in our understanding of the development and function of this crucial T cell subset. Our preliminary studies suggested that a substantial proportion of Treg is specific for ubiquitously expressed class II-bound peptides present in high copy numbers. Based on these data and our recent observation of MHC class II-dependent proliferation of Treg in a lymphopenic host, we further hypothesize that Treg TCR interactions with the MHC-peptide ligands are required for the peripheral maintenance of the Treg subset and its function. In this proposal, we will test these hypotheses by characterizing Treg specificity, and by further investigating requirements for self-peptide recognition for Treg development in the thymus and for their function in the periphery. In the former experiments we will attempt a direct identification of the peptide-MHC class II complexes recognized by Treg TCR. In the latter studies, we will be using transgenic Treg TCR selected in "single peptide" mice and in mice with a wild type repertoire of class II-bound self peptides, as well as polyclonal Treg from "single peptide" mice. These studies will provide new information on the role of Treg recognition of specific MHC class II-bound peptides in Treg thymic development, maintenance in the periphery, and in Treg-mediated protection against autoimmunity. This knowledge is of principal importance for understanding of Treg biology and for developing Treg cell therapies to alleviate autoimmunity and transplant rejection.