[Foreign and self--the challenge for the immune system]

This process of thymic selection produces a repertoire of T-cells able to recognize foreign antigens but to remain nonreactive to the body's own antigens, designated "self" (central tolerance). The interaction between lymphoid and stromal cells within the thymic microenvironment is critical in order to shape the correct antigen specificity of the T-cell repertoire. The thymus has been regarded as the main site of tolerance induction to ubiquitous self-antigens, i.e. abundant blood-borne self-antigens or proteins that are expressed by thymic cells. In contrast, tolerance to ubiquitous, i.e. tissue-restricted, self-antigens has been attributed to extrathymic, peripheral mechanisms. Here I review scientific evidence which assigns a much larger role for the thymus in tissue-specific tolerance. The reason for this paradigmatic shift is, first, the discovery of ectopic expression of tissue-restricted self-antigens by thymic medullary epithelial cells (TECs) which thus present to developing T-cells a "molecular mirror of peripheral self". As a consequence, central tolerance to many peripheral self-antigens can be generated. Second, the thymus is capable to produce regulatory T-cells. Such CD4+CD25+Foxp3+ T-cells are selected by antigens presented by medullary TECs and can control in the periphery the activation of tissue-specific self-reactive T-cells by use of active inhibitory mechanisms. These new insights have implications for our understanding of self-tolerance and its breakdown in autoimmune diseases.