Key Points
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Autoimmune regulator (AIRE) protein is mainly expressed by mature medullary thymic epithelial cells, in which it promotes the promiscuous expression of many tissue-specific antigens (TSAs).
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TSAs that are upregulated by AIRE are presented to developing thymocytes, and this is required for efficient negative selection. Aberrant negative selection in the absence of AIRE leads to the escape of self-reactive thymocytes to the periphery and subsequent autoimmunity.
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AIRE contains several domains that are characteristic of transcriptional regulators and chromatin-binding proteins, such as a caspase-recruitment domain (CARD), a SP100, AIRE1, NucP41/P75 and DEAF1 (SAND) domain and plant homeodomain (PHD) zinc fingers. Concordantly, many studies have confirmed that AIRE is as a potent transcriptional activator.
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Several proteins have been found to interact with AIRE, including CREB-binding protein (CBP), protein inhibitor of activated STAT1 (PIAS1), DNA-dependent protein kinase (DNA-PK), histone H3 unmethylated at lysine 4 and the positive transcription elongation factor b (P-TEFb).
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Interaction with histone H3 that is unmethylated at lysine 4 allows AIRE to bind to certain chromatin regions. At target gene promoters, AIRE promotes transcriptional elongation by binding and recruiting the P-TEFb complex to RNA polymerase II.
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AIRE-regulated genes tend to cluster in the genome; however, recent findings indicate that at a single-cell level, the expression of TSAs varies, which suggests that gene activation by AIRE can be a stochastic event.
Abstract
The negative selection of T cells in the thymus is necessary for the maintenance of self tolerance. Medullary thymic epithelial cells have a key function in this process as they express a large number of tissue-specific self antigens that are presented to developing T cells. Mutations in the autoimmune regulator (AIRE) protein cause a breakdown of central tolerance that is associated with decreased expression of self antigens in the thymus. In this Review, we discuss the role of AIRE in the thymus and recent advances in our understanding of how AIRE might function at the molecular level to regulate gene expression.
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Acknowledgements
We would like to thank all laboratory members and many colleagues including M. Anderson, G. Holländer, K. Krohn, O. Kämpe, B. Kyewski, A. Marx, M. Matsumoto, G. Musco, T. Rich, H. Scott, I. Ulmanen and N. Willcox for useful discussions. This work was supported by EU FP6 project Thymaide, The Wellcome Trust, European Regional Development Fund and Estonian Science Foundation.
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Glossary
- Central tolerance
-
The lack of self responsiveness that occurs during lymphocyte development in the central lymphoid organs. B-cell progenitors in the bone marrow and T-cell progenitors in the thymus that strongly recognize self antigen either undergo further rearrangement of antigen-receptor genes to avoid reactivity to self or face deletion by apoptosis.
- Negative selection
-
The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self peptide bound to self MHC molecules undergo apoptosis in response to the signalling that is generated by high-affinity binding of their target antigen presented by cells in the thymic medulla.
- Penetrance
-
The proportion of affected individuals among carriers of a particular genotype. If all individuals with a disease genotype have the disease phenotype, then the disease is said to be completely penetrant.
- Söjgren's syndrome
-
An organ-specific autoimmune disorder that is characterized by lymphocytic infiltrates, tissue destruction and functional decline of salivary or lacrimal glands, and the systemic production of autoantibodies specific for ribonucleoproteins.
- Non-obese diabetic (NOD) mice
-
NOD mice develop spontaneous diabetes, including the development of islet-specific autoantibodies and inflammation of the pancreatic islets.
- Tight junction
-
A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.
- Caspase-recruitment domain
-
A protein domain that is found in certain initiator caspases (for example, mammalian caspase 9) and their adaptor proteins (for example, APAF1) that function in inflammation and apoptosis. This domain mediates protein–protein interactions.
- PHD zinc finger
-
A domain that consists of about 60 amino acids and are characterized by a C4HC3 (four cysteines, one histidine, three cysteines) signature that binds two zinc ions. It has been shown recently to bind to histone H3 modified or unmodified at specific residues.
- Nuclear bodies
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Structurally and functionally heterogeneous subnuclear structures (0.2–1μm) that are present in most mammalian cells and that have been implicated in cellular senescence, apoptosis, proliferation and maintenance of genomic stability through transcriptional repression, transcriptional activation and protein degradation.
- Nuclear speckles
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Dynamic subnuclear structures that contain pre-mRNA splicing factors and other proteins that are involved in transcription, 3′-end RNA processing and reversible protein phosphorylation.
- Nuclear matrix
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A network of nuclear proteins that provides a structural framework for chromatin organization.
- Enhancer
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A region of DNA that can bind activator proteins, which can initiate the transcription of a gene promoter that is a long distance from the enhancer.
- Insulator
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A boundary element in the genome that can block the activity of nearby enhancer regions or function as a barrier against heterochromatin spreading into active chromatin areas.
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Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol 8, 948–957 (2008). https://doi.org/10.1038/nri2450
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DOI: https://doi.org/10.1038/nri2450
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