AIRE expands: new roles in immune tolerance and beyond

Abstract

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 immune tolerance.

Figure 1

Disease-causing Aire mutations in patients with classic and non-classic APS-1. A) The wildtype (WT) Aire protein with its domains (top). Dominant Aire mutations (X) and 5 representative recessive Aire mutations (triangle) from more than 100 recessive mutations described are shown below. Dominant mutations cluster in the PHD1 domain whereas recessive mutations are found throughout the Aire protein, including the HSR/CARD multimerization domain. B) Mutant Aire proteins and how they can cause disease. Classic APS-1 can occur with homozygous Aire R257X mutations (upper le]). These mutant Aire proteins can multimerize but lack critical Aire domains. Alternatively, compound heterozygotes with HSR/CARD domain mutant (R15L) that prevents multimerization and truncation mutant (C322del13) (lower left) can also lead to classic APS-1. Non-classic APS-1 occurs with one copy of an Aire C111Y or G228W mutation (right).

Figure 2

Ordered stochasticasticity of Aire regulated gene expression. Aire-regulated TSA expression in single mTEC does not occur randomly but occur in microclusters of co-expression. Interchromosomal clusters of TSA expression are shown, although clustering of genes located in close proximity in the genome has also been demonstrated. “Bookmarking”, or the maintenance of gene-expression programs after cell division, may result in the clonal expansion of mTECs expressing TSA microclusters (left).

Figure 3

Aire and it’s binding partners. A) Schematic illustration of a partial set of Aire's interacting partners. Dozens of Aire interacting partners with diverse functions have been identified. Here is shown Aire's ineractions with histone core proteins either directly or through its interactions with DNA-PK; ATF7ip/MBDl/ESET complex that interacts with methylated DNA; and pTEFb, HnRNPL and RNA pol2 to release stalled polyermases. Aire also interacts with Sirtl and CBP which control Aire aceytlation. B) Map of regions of Aire that interact with binding partners.

Figure 3

Aire and it’s binding partners. A) Schematic illustration of a partial set of Aire's interacting partners. Dozens of Aire interacting partners with diverse functions have been identified. Here is shown Aire's ineractions with histone core proteins either directly or through its interactions with DNA-PK; ATF7ip/MBDl/ESET complex that interacts with methylated DNA; and pTEFb, HnRNPL and RNA pol2 to release stalled polyermases. Aire also interacts with Sirtl and CBP which control Aire aceytlation. B) Map of regions of Aire that interact with binding partners.

Figure 4. Aire enforces central tolerance toward self-antigens

A) In wildtype thymus, Aire in medullary thymic epithelial cells (mTECs), promotes ectopic expression of self-antigens (Ag), which include melanoma Ags. T cells recognizing these antigens undergo negative selection to enforce self-tolerance. B) In Aire deficienct thymus or thymus treated with anti-RANKL antibody, lack of self-antigen expression allows escape of self-reactive T cells from negative selection, which predisposes to autoimmunity.