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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.

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.

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Figure 1: AIRE mutations associated with autoimmune disease.
Figure 2: AIRE-regulated TSA expression is 'stochastic' and 'ordered'.
Figure 3: AIRE and its binding partners.
Figure 4: The various functions of AIRE in mTECs.
Figure 5: AIRE enforces central tolerance towards self-antigens.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health to both M.S.A. and M.A.S.

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Glossary

Autoimmune polyglandular syndrome type 1

(APS1). A rare human autoimmune disorder that is inherited in an autosomal recessive manner and is characterized by various endocrine deficiencies, chronic mucocutaneous candidiasis and ectodermal dystrophies. It is caused by mutations in the gene that encodes autoimmune regulator (AIRE).

Co-immunoprecipitation

A protein purification experiment used to identify proteins that are in complex with each other.

Yeast two-hybrid screening

A screening system for protein–protein interactions that results in the transcription of a reporter gene when a bait protein attached to a DNA-binding domain comes into contact with a prey protein bound to a transcriptional activator.

RNA interference

(RNAi). A phenomenon in which the expression of a gene is inhibited when a double-stranded complementary RNA is introduced into the organism.

Silenced chromatin states

Regions of chromatin that are in a repressed or silenced state, such that genes in these regions are not expressed.

Morisita–Horn similarity index

A statistical algorithm that is used to determine the similarity of complex sequences, such as those seen in individual T cell receptors.

Graft-versus-host disease

(GVHD). A potentially serious complication arising when donor-derived T cells attack host tissues, typically resulting in hepatic, dermatological and gastrointestinal damage. Acute GVHD occurs within the first 100 days after transplantation, whereas chronic GVHD occurs later and has a different pathophysiology.

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Anderson, M., Su, M. AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol 16, 247–258 (2016). https://doi.org/10.1038/nri.2016.9

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