SELF PEPTIDES BOUND TO MHC CLASS II IN T CELL SELECTION

描述(申请人提供)：尽管胸腺细胞受到严格的质量控制，但胸腺中的阳性和阴性选择，一些自身反应性T细胞逃逸到外围。CD25+CD4调节性T细胞(Treg)在预防自身免疫中起着关键作用。最近观察到，在共表达转基因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类结合多肽的亲和力增加。然而，TCR的多肽特异性在自然产生的Treg中表达，以及在Treg分化的不同阶段识别特定的自体多肽的要求仍然是该领域的一个主要未知因素。这种知识的缺乏阻碍了我们对这一关键T细胞亚群的发展和功能的进一步了解。我们的初步研究表明，相当大比例的Treg是针对以高拷贝数存在的普遍表达的II类结合多肽。基于这些数据和我们最近观察到的依赖于MHC II类的Treg在淋巴细胞减少的宿主中的增殖，我们进一步假设Treg TCR与MHC多肽配体的相互作用是Treg亚群及其功能的外周维持所必需的。在这项提案中，我们将通过表征Treg的特异性，并通过进一步研究胸腺Treg发育及其外周功能对自体多肽识别的要求来检验这些假设。在前面的实验中，我们将尝试直接鉴定由Treg TCR识别的多肽-MHC II类复合体。在后一项研究中，我们将使用从“单肽”小鼠和具有II类结合自体多肽的野生型谱系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。这些研究将提供有关Treg识别特定MHC II类结合多肽在Treg胸腺发育、外周维持以及Treg介导的自身免疫保护中的作用的新信息。这些知识对于了解Treg生物学和开发Treg细胞疗法以减轻自身免疫和移植排斥反应具有重要意义。

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.