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

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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.