The many faces of Aire in central tolerance

Although the role that Autoimmune Regulator (Aire) plays in the induction of central tolerance is well known, the precise cellular and molecular mechanisms are still unclear and debated. In the prevailing view, Aire serves mainly as a direct inducer of tissue-specific antigens (TSAs). However, there is a growing amount of evidence suggesting that Aire modulates the differentiation program of medullary thymic epithelial cells (mTECs), which may directly contribute to the negative selection of self-reactive thymocytes. In addition, Aire has been shown to regulate the expression of many intrathymic chemokines that are required for the proper localization of thymocytes and dendritic cells (DCs), and thus are potentially important for direct and indirect self-antigen presentation in the thymic medulla. Further, recent evidence suggests that the induction of certain antigen-specific Tregs that translocate to tumors and peripheral tissues can be Aire dependent and may contribute to tissue-specific tolerance. This review summarizes the current understanding of the effects of Aire on these alternative mechanisms for the induction of Aire-induced central tolerance.