Exploring the tolerogenic function of medullary thymic epithelial cells using tissue-specific knockdown in transgenic mice

对“自我”的耐受性是T细胞谱系的基本属性。在胸腺内自身抗原遭遇时自身反应性T细胞的消除或功能性重编程，所谓的"中枢耐受"，对于预防自身免疫是必不可少的。基于发现许多"组织限制性抗原"（TRAs）在胸腺内表达，现在普遍认为中枢耐受涵盖了比以前预期的更广泛的自身抗原谱。异位TRA表达是胸腺髓质上皮细胞（mTECs）的独特性质，其缺乏导致自发性自身免疫，强调mTECs作为"抗原生产者"的重要作用。重要的是，mTEC衍生的自身抗原可以被胸腺树突细胞摄取以呈递给发育中的T细胞。因此，目前尚不清楚mTEC是否除了抗原产生之外，还履行作为致耐受性抗原呈递细胞的非冗余作用，如果是这样，mTEC上的抗原识别是否有利于缺失或非缺失的耐受模式。为了在CD4 T细胞耐受的背景下解决这个问题，必须干扰mTEC在MHC II上呈递抗原的能力，同时保持TRA表达完整。小鼠模型的生成和分析，以实现这一目标是本提案的主题。

Tolerance to “self” is a fundamental property of the T cell repertoire. Elimination or functional reprogramming of autoreactive T cells upon intrathymic self-antigen encounter, so-called “central tolerance”, is essential to prevent autoimmunity. Based upon the discovery that numerous “tissue restricted antigens” (TRAs) are expressed within the thymus, it is now generally accepted that central tolerance covers a much wider spectrum of self-antigens than previously anticipated. Ectopic TRA-expression is a unique property of medullary thymic epithelial cells (mTECs), and its lack results in spontaneous autoimmunity, emphasizing the essential role of mTECs as “antigen producers”. Importantly, mTEC-derived self-antigens may be taken up by thymic dendritic cells for presentation to developing T cells. Therefore, it remains unclear whether mTECs, besides antigen production, in addition fulfill a nonredundant role as tolerogenic antigen presenting cells, and if so, whether recognition of antigen on mTEC favors deletional or non-deletional modes of tolerance. To address this issue in the context of CD4 T cell tolerance, one would have to interfere with the capacity of mTEC to present antigens on MHC II while leaving TRA expression intact. The generation and analysis of mouse models to achieve this goal is subject of the present proposal.