AIRE expands: new roles in immune tolerance and beyond

Key Points Autoimmune regulator (AIRE) has a well-known role in preventing autoimmunity through upregulation of tissue-specific antigen (TSA) expression in medullary thymic epithelial cells (mTECs). Recognition of these thymic TSAs by self-reactive T cells leads to clonal deletion and/or diversion to the regulatory T cell lineage. Mutations in AIRE result in multi-organ autoimmune disease in both humans and mice. In humans, autosomal recessive mutations result in autoimmune polyendocrinopathy syndrome 1, whereas dominant mutations result in autoimmunity with a more narrow disease spectrum. AIRE expression is under strict spatiotemporal control. Regulation of AIRE expression is achieved through several mechanisms, including enhancer elements that regulate the transcription and alternative splicing of AIRE , which in turn control AIRE protein levels. The array of TSAs expressed by each individual mTEC is diverse. Nevertheless, clusters of TSAs are co-expressed, with distinct rules governing their co-expression. AIRE interacts with dozens of proteins with various functions, including the recruitment of AIRE to TSA genes, elongation of AIRE-dependent TSA transcripts and modification of AIRE itself. AIRE has important roles in conditions beyond autoimmunity, such as graft-versus-host disease and cancer. Thus, modulation of AIRE function may have potential therapeutic benefit in a wide range of diseases. Autoimmune regulator (AIRE) is best known for its role in immune tolerance. In this Review, the authors summarize the recent advances in our understanding of the diverse functions of AIRE, including its role in selection of regulatory T cells and modulation of non-autoimmune diseases. More than 15 years ago, mutations in the autoimmune regulator ( AIRE ) gene were identified as the cause of autoimmune polyglandular syndrome type 1 (APS1). It is now clear that this transcription factor has a crucial role in promoting self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery. In this Review, we highlight many of the recent advances in our understanding of the complex biology that is related to AIRE, with a particular focus on advances in genetics, molecular interactions and the effect of AIRE on thymic selection of regulatory T cells. Furthermore, we highlight new areas of biology that are potentially affected by this key regulator of