The fate of developing T cells is specified by interactions of their antigen receptor with self-peptide/MHC complexes displayed by thymic antigen presenting cells (APCs). Various thymic APCs subsets are strategically positioned in particular thymic microenvironments and orchestrate the selection of a functional and self-tolerant T cell repertoire. Here, we will review the different strategies that these APCs employ to sample and process self-antigens and thereby generate partly unique, ‘idiosyncratic’ peptide/MHC ligandomes. We will discuss how the particular composition of these APC-subset-specific peptide/MHC ligandomes not only shapes the T cell repertoire in the thymus, but may also indelibly imprint the behavior of mature T cells in the periphery.

Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens.

Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.