AIRE – The Autoimmune Regulator


Autoimmune diseases, caused by continuous immune responses against self‐antigens, have an uncertain aetiology. Although breakdown of self‐tolerance is considered to be the key event in the disease process, the underlying mechanisms are still enigmatic. So far, only a small number of genes that seem to be relevant to the pathogenesis of autoimmune diseases have been found. One of these genes is the autoimmune regulator (AIRE), mutation in which is responsible for the development of autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) showing autosomal recessive inheritance. AIRE is a transcriptional regulator expressed predominantly by medullary thymic epithelial cells. Elucidation of how defective function of AIRE results in the development of organ‐specific autoimmunity is expected to shed light on not only the pathogenesis of autoimmune disease but also the fundamental question of how the immune system is educated to discriminate between self and nonself in the thymus.

Key Concepts

  • Autoimmune regulator (AIRE) is responsible for the development of organ‐specific autoimmune disease in a monogenic fashion.
  • AIRE is expressed predominantly by thymic stromal cells (medullary thymic epithelial cells: mTECs) and controls the negative selection and production of regulatory T cells in the thymus.
  • Production of a wide variety of autoantibodies (e.g. anti‐IFNs and anti‐Th17 cytokines) associated with autoimmune pathology and/or candidiasis infection is a prominent feature of AIRE deficiency.
  • AIRE deficiency results in reduced transcription of a wide variety of tissue‐restricted antigen genes by mTECs.
  • AIRE regulates the differentiation program of mTECs.
  • Elucidation of AIRE function is expected to clarify the fundamental issue of how the immune system discriminates self from nonself.
  • Identification of the target genes controlled by AIRE is essential for clarifying the exact function of AIRE in self‐tolerance.

Keywords: AIRE ; autoimmune disease; thymus; medullary thymic epithelial cell (mTEC); central tolerance; tissue‐restricted antigen; promiscuous gene expression; knockout mouse; negative selection; regulatory T cell

Figure 1. Genomic organisation of human AIRE. (a) The human AIRE gene is located on the long arm of chromosome 21 (21q22.3). (b, c) AIRE encodes a predicted 58‐kDa protein carrying a homogeneously staining region (HSR), a conserved nuclear localisation signal (NLS), the Sp100, AIRE, NucP41/75 region and Deaf1 (SAND) domain and two plant homeodomain (PHD)‐type zinc fingers. The PHD1 domain has been demonstrated to bind preferentially with the unmethylated H3K4 histone tail (H3K4me0).
Figure 2. mTECs expressing Aire protein in mice. (a) The location of mTECs expressing Aire protein demonstrated by the use of an Aire‐reporter strain (Aire/GFP knock‐in mice) (Yano et al., ). One thymic medulla immunostained with anti‐keratin 5 (red) is shown. Because of the nature of GFP protein, Aire+ mTECs are marked with GFP (stained green) throughout, including the cytoplasm. Scale bar: 100 µm. (b) Endogenous Aire protein in mice stained with anti‐Aire antibody (red) appearing as nuclear dots. Staining with anti‐keratin 5 reveals the dendritic‐cell shapes of mTECs (green). Scale bar: 10 µm.
Figure 3. Impaired central tolerance due to lack of Aire. Immature thymocytes at the double‐negative (DN) stages (DN1‐4) mature to the double‐positive (DP) stage in the cortex (upper), where thymocytes recognising the peptide/MHC complex survive (positive selection). These develop into single‐positive cells (SP) and migrate to the medulla (lower). In wild‐type mice (lower left), SP cells interacting with TRAs with high affinity (+++) die due to apoptosis (negative selection). Although not depicted in this scheme, TRAs may be presented by DCs after being transferred from mTECs in an Aire‐dependent manner (Figure ). SP cells interacting with TRAs with intermediate affinity (++) become Tregs. SP cells interacting only weakly with TRAs (+) can become effector T cells to protect the body. In Aire‐deficient mice (lower right), negative selection and the production of Tregs are impaired, most likely due to the reduction in TRAs at the transcriptional level.
Figure 4. Alteration in the program of mTEC differentiation due to lack of Aire. mTECs develop from their progenitors through three stages characterised by the levels of CD80 and/or MHC‐II expression (not depicted). In wild‐type mice (upper), immature mTECs receive cytokine signals (RANKL, CD40L and LT) provided by lymphoid‐tissue inducer (LTi) and thymocytes to become mature mTECs (upper center) expressing many TRAs supported by Aire. The level of CD80 expression is highest at this stage. The cells eventually lose their ability to express Aire together with many TRAs (post‐Aire) with a concomitant increase in the expression of keratinocyte‐related molecules such as involucrin. Then, they either die or form Hassall's bodies (HB) just before cell death. In the absence of Aire (lower), mTECs do not undergo the normal differentiation program, showing more globular cell shapes and reduced TRA transcription. Their CD80 level remains rather high until they die in the absence of Aire. Nevertheless, the half‐life of mTECs lacking Aire is indistinguishable from that of wild‐type mTECs.
Figure 5. Aire‐dependent antigen transfer from mTECs to BM‐APCs. In the RIP‐OVA Tg model, where immature mTEClow express self‐Ag (OVA), OVA must be transferred to BM‐APCs (i.e. thymic DCs and thymic B cells), which is an Aire‐dependent process, to elicit clonal deletion (negative selection) and Treg production. However, Tregs can be also induced directly by mTEChigh expressing OVA in an Aire‐dependent manner. In contrast, both OVA and Aire expressed by BM‐APCs are irrelevant to these processes in this transgenic model. Originally published in The Journal of Immunology. Mouri, Y., Ueda, Y., Yamano, T., Matsumoto, M., Tsuneyama, K., Kinashi, T., and Matsumoto, M. 2017. Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self‐Antigen and Those That Present Antigen. J. Immunol. Copyright © [2017] The American Association of Immunologists, Inc.


Abramson J and Anderson G (2017) Thymic epithelial cells. Annual Review of Immunology 35: 85–118.

Abramson J , Giraud M , Benoist C and Mathis D (2010) Aire's partners in the molecular control of immunological tolerance. Cell 140: 123–135.

Akiyoshi H , Hatakeyama S , Pitkanen J , et al. (2004) Subcellular expression of autoimmune regulator (AIRE) is organized in a spatiotemporal manner. Journal of Biological Chemistry 279: 33984–33991.

Anderson MS and Su MA (2016) AIRE expands: new roles in immune tolerance and beyond. Nature Reviews Immunology 16: 247–258.

Anderson MS , Venanzi ES , Chen Z , et al. (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23: 227–239.

Anderson MS , Venanzi ES , Klein L , et al. (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298: 1395–1401.

Aschenbrenner K , D'Cruz LM , Vollmann EH , et al. (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nature Immunology 8: 351–358.

Chuprin A , Avin A , Goldfarb Y , et al. (2015) The deacetylase Sirt1 is an essential regulator of Aire‐mediated induction of central immunological tolerance. Nature Immunology 16: 737–745.

Consortium TF‐GA (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD‐type zinc‐finger domains. Nature Genetics 17: 399–403.

Derbinski J , Schulte A , Kyewski B and Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunology 2: 1032–1039.

Edelson BT , Kc W , Juang R , et al. (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. Journal of Experimental Medicine 207: 823–836.

Ferre EM , Rose SR , Rosenzweig SD , et al. (2016) Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy. JCI Insight 1: e88782.

Fishman D , Kisand K , Hertel C , et al. (2017) Autoantibody repertoire in APECED patients targets two distinct subgroups of proteins. Frontiers in Immunology 8: 976.

Gardner JM , Metzger TC , McMahon EJ , et al. (2013) Extrathymic Aire‐expressing cells are a distinct bone marrow‐derived population that induce functional inactivation of CD4(+) T cells. Immunity 39: 560–572.

Gillard GO , Dooley J , Erickson M , Peltonen L and Farr AG (2007) Aire‐dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. Journal of Immunology 178: 3007–3015.

Giraud M , Jmari N , Du L , et al. (2014) An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire‐activated ectopic transcription. Proceedings of the National Academy of Sciences of the United States of America 111: 1491–1496.

Hanahan D (1998) Peripheral‐antigen‐expressing cells in thymic medulla: factors in self‐tolerance and autoimmunity. Current Opinion in Immunology 10: 656–662.

Hobbs RP , DePianto DJ , Jacob JT , et al. (2015) Keratin‐dependent regulation of Aire and gene expression in skin tumor keratinocytes. Nature Genetics 47: 933–938.

Hubert FX , Kinkel SA , Davey GM , et al. (2011) Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118: 2462–2472.

Kawano H , Nishijima H , Morimoto J , et al. (2015) Aire expression is inherent to most medullary thymic epithelial cells during their differentiation program. Journal of Immunology 195: 5149–5158.

Kisand K , Boe Wolff AS , Podkrajsek KT , et al. (2010) Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17‐associated cytokines. Journal of Experimental Medicine 207: 299–308.

Kisand K , Link M , Wolff AS , et al. (2008) Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN‐stimulated genes. Blood 112: 2657–2666.

Klein L , Kyewski B , Allen PM and Hogquist KA (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nature Reviews Immunology 14: 377–391.

Koh AS , Miller EL , Buenrostro JD , et al. (2018) Rapid chromatin repression by Aire provides precise control of immune tolerance. Nature Immunology 19: 162–172.

Kuroda N , Mitani T , Takeda N , et al. (2005) Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire‐deficient mice. Journal of Immunology 174: 1862–1870.

Kyewski B and Klein L (2006) A central role for central tolerance. Annual Review of Immunology 24: 571–606.

Liston A , Lesage S , Wilson J , Peltonen L and Goodnow CC (2003) Aire regulates negative selection of organ‐specific T cells. Nature Immunology 4: 350–354.

Malchow S , Leventhal DS , Nishi S , et al. (2013) Aire‐dependent thymic development of tumor‐associated regulatory T cells. Science 339: 1219–1224.

Mathis D and Benoist C (2009) Aire. Annual Review of Immunology 27: 287–312.

Matsumoto M (2011) Contrasting models for the roles of Aire in the differentiation program of epithelial cells in the thymic medulla. European Journal of Immunology 41: 12–17.

Meager A , Visvalingam K , Peterson P , et al. (2006) Anti‐interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Medicine 3: e289.

Metzger TC , Khan IS , Gardner JM , et al. (2013) Lineage tracing and cell ablation identify a post‐Aire‐expressing thymic epithelial cell population. Cell Reports 5: 166–179.

Meyer S , Woodward M , Hertel C , et al. (2016) AIRE‐deficient patients harbor unique high‐affinity disease‐ameliorating autoantibodies. Cell 166: 582–595.

Mouri Y , Ueda Y , Yamano T , et al. (2017) Mode of tolerance induction and requirement for Aire are governed by the cell types that express self‐antigen and those that present antigen. Journal of Immunology 199: 3959–3971.

Nagamine K , Peterson P , Scott HS , et al. (1997) Positional cloning of the APECED gene. Nature Genetics 17: 393–398.

Niki S , Oshikawa K , Mouri Y , et al. (2006) Alteration of intra‐pancreatic target‐organ specificity by abrogation of Aire in NOD mice. Journal of Clinical Investigation 116: 1292–1301.

Nishijima H , Kajimoto T , Matsuoka Y , et al. (2018) Paradoxical development of polymyositis‐like autoimmunity through augmented expression of autoimmune regulator (AIRE). Journal of Autoimmunity 86: 75–92.

Nishijima H , Kitano S , Miyachi H , et al. (2015) Ectopic aire expression in the thymic cortex reveals inherent properties of aire as a tolerogenic factor within the medulla. Journal of Immunology 195: 4641–4649.

Nishikawa Y , Hirota F , Yano M , et al. (2010) Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end‐stage terminal differentiation. Journal of Experimental Medicine 207: 963–971.

Nishikawa Y , Nishijima H , Matsumoto M , et al. (2014) Temporal lineage tracing of Aire‐expressing cells reveals a requirement for Aire in their maturation program. Journal of Immunology 192: 2585–2592.

Org T , Rebane A , Kisand K , et al. (2009) AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Human Molecular Genetics 18: 4699–4710.

Perry JS , Lio CW , Kau AL , et al. (2014) Distinct contributions of Aire and antigen‐presenting‐cell subsets to the generation of self‐tolerance in the thymus. Immunity 41: 414–426.

Sansom SN , Shikama‐Dorn N , Zhanybekova S , et al. (2014) Population and single‐cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self‐antigen expression in thymic epithelia. Genome Research 24: 1918–1931.

Skogberg G , Lundberg V , Lindgren S , et al. (2014) Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype. Journal of Immunology 193: 2187–2195.

Takaba H , Morishita Y , Tomofuji Y , et al. (2015) Fezf2 orchestrates a thymic program of self‐antigen expression for immune tolerance. Cell 163: 975–987.

Wang X , Laan M , Bichele R , et al. (2012) Post‐Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte‐specific autoantigens. Frontiers in Immunology 3: 19.

Yamano T , Nedjic J , Hinterberger M , et al. (2015) Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42: 1048–1061.

Yang S , Fujikado N , Kolodin D , Benoist C and Mathis D (2015) Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self‐tolerance. Science 348: 589–594.

Yano M , Kuroda N , Han H , et al. (2008) Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self‐tolerance. Journal of Experimental Medicine 205: 2827–2838.

Zumer K , Saksela K and Peterlin BM (2013) The mechanism of tissue‐restricted antigen gene expression by AIRE. Journal of Immunology 190: 2479–2482.

Further Reading

Alves NL , Takahama Y , Ohigashi I , et al. (2014) Serial progression of cortical and medullary thymic epithelial microenvironments. European Journal of Immunology 44: 16–22.

Bornstein C , Nevo S , Giladi A , et al. (2018) Single‐cell mapping of the thymic stroma identifies IL‐25‐producing tuft epithelial cells. Nature 559: 622–626.

Brennecke P , Reyes A , Pinto S , et al. (2015) Single‐cell transcriptome analysis reveals coordinated ectopic gene‐expression patterns in medullary thymic epithelial cells. Nature Immunology 16: 933–941.

Kernfeld EM , Genga RMJ , Neherin K , et al. (2018) A Single‐cell transcriptomic atlas of thymus organogenesis resolves cell types and developmental maturation. Immunity 48: 1258–1270 e1256.

Matsumoto M , Nishikawa Y , Nishijima H , et al. (2013) Which model better fits the role of aire in the establishment of self‐tolerance: the transcription model or the maturation model? Frontiers in Immunology 4: 210.

Meredith M , Zemmour D , Mathis D and Benoist C (2015) Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nature Immunology 16: 942–949.

Miller CN , Proekt I , von Moltke J , et al. (2018) Thymic tuft cells promote an IL‐4‐enriched medulla and shape thymocyte development. Nature 559: 627–631.

Perry JSA , Russler‐Germain EV , Zhou YW , et al. (2018) Transfer of cell‐surface antigens by scavenger receptor CD36 promotes thymic regulatory T cell receptor repertoire development and allo‐tolerance. Immunity 48: 1271.

Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self‐tolerance and negative control of immune responses. Annual Review of Immunology 22: 531–562.

Sekai M , Hamazaki Y and Minato N (2014) Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance. Immunity 41: 753–761.

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Matsumoto, Minoru, Nishijima, Hitoshi, Morimoto, Junko, Tsuneyama, Koichi, and Matsumoto, Mitsuru(Feb 2019) AIRE – The Autoimmune Regulator. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027281]