Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.

Laboratory of Immunobiology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

Finnish-German AC. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17(4):399–403. DOI

Nagamine K, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17(4):393–8. PubMed DOI

Anderson MS, et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science. 2002;298(5597):1395–401. PubMed DOI

Abramson J, et al. Aire’s partners in the molecular control of immunological tolerance. Cell. 2010;140(1):123–35. PubMed DOI

Klein L, et al. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol. 2014;14(6):377–91. PubMed DOI PMC

Abramson J, Husebye ES. Autoimmune regulator and self-tolerance—molecular and clinical aspects. Immunol Rev. 2016;271(1):127–40. PubMed DOI

Bansal K, et al. The transcriptional regulator Aire binds to and activates super-enhancers. Nat Immunol. 2017;18(3):263–73. PubMed DOI PMC

Sansom SN, et al. Population and single-cell genomics reveal the Aire dependency, relief from polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res. 2014;24(12):1918–31. PubMed DOI PMC

Brennecke P, et al. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat Immunol. 2015;16(9):933–41. PubMed DOI PMC

Meredith M, et al. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol. 2015;16(9):942–9. PubMed DOI PMC

Danan-Gotthold M, et al. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 2016;17(1):219. PubMed DOI PMC

Husebye ES, Anderson MS, Kampe O. Autoimmune polyendocrine syndromes. N Engl J Med. 2018;378(12):1132–41. PubMed DOI PMC

Ramsey C, et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet. 2002;11(4):397–409. PubMed DOI

Kuroda N, et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol. 2005;174(4):1862–70. PubMed DOI

Pontynen N, et al. Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients. J Autoimmun. 2006;27(2):96–104. PubMed DOI

Lohse AW, et al. Estimation of the frequency of self-reactive T cells in health and inflammatory diseases by limiting dilution analysis and single cell cloning. J Autoimmun. 1996;9(5):667–75. PubMed DOI

Gallegos AM, Bevan MJ. Central tolerance: good but imperfect. Immunol Rev. 2006;209:290–6. PubMed DOI

Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol. 2010;11(1):21–7. PubMed DOI

ElTanbouly MA, Noelle RJ. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat Rev Immunol. 2021;21(4):257–67. PubMed DOI

Mathis D, Benoist C. A decade of AIRE. Nat Rev Immunol. 2007;7(8):645–50. PubMed DOI

Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91(8):2843–50. PubMed DOI

Heino M, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257(3):821–5. PubMed DOI

Suzuki E, et al. Expression of AIRE in thymocytes and peripheral lymphocytes. Autoimmunity. 2008;41(2):133–9. PubMed DOI

Pontynen N, et al. Critical immunological pathways are downregulated in APECED patient dendritic cells. J Mol Med (Berl). 2008;86(10):1139–52. PubMed DOI

Poliani PL, et al. Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am J Pathol. 2010;176(3):1104–12. PubMed DOI PMC

Ruan QG, et al. Expression and alternative splicing of the mouse autoimmune regulator gene (Aire). J Autoimmun. 1999;13(3):307–13. PubMed DOI

Zuklys S, et al. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J Immunol. 2000;165(4):1976–83. PubMed DOI

Heino M, et al. RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse. Eur J Immunol. 2000;30(7):1884–93. PubMed DOI

Halonen M, et al. Subcellular location and expression pattern of autoimmune regulator (Aire), the mouse orthologue for human gene defective in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). J Histochem Cytochem. 2001;49(2):197–208. PubMed DOI

Adamson KA, et al. A comparative study of mRNA and protein expression of the autoimmune regulator gene (Aire) in embryonic and adult murine tissues. J Pathol. 2004;202(2):180–7. PubMed DOI

Zheng X, et al. Expression of tissue-specific autoantigens in the hematopoietic cells leads to activation-induced cell death of autoreactive T cells in the secondary lymphoid organs. Eur J Immunol. 2004;34(11):3126–34. PubMed DOI

Lee JW, et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007;8(2):181–90. PubMed DOI

Schaller CE, et al. Expression of Aire and the early wave of apoptosis in spermatogenesis. J Immunol. 2008;180(3):1338–43. PubMed DOI

Hubert FX, et al. A specific anti-Aire antibody reveals Aire expression is restricted to medullary thymic epithelial cells and not expressed in periphery. J Immunol. 2008;180(6):3824–32. PubMed DOI

Cohen JN, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med. 2010;207(4):681–8. PubMed DOI PMC

Fletcher AL, et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207(4):689–97. PubMed DOI PMC

Eldershaw SA, Sansom DM, Narendran P. Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue. Clin Exp Immunol. 2011;163(3):296–308. PubMed DOI PMC

Saltis M, et al. Evolutionarily conserved and divergent regions of the autoimmune regulator (Aire) gene: a comparative analysis. Immunogenetics. 2008;60(2):105–14. PubMed DOI PMC

Lindmark E, et al. AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment. J Autoimmun. 2013;42:62–70. PubMed DOI

Garcia CA, et al. Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion. J Immunol. 2005;175(4):2111–22. PubMed DOI

Pugliese A, et al. Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J Clin Invest. 2001;107(5):555–64. PubMed DOI PMC

Magnusson FC, et al. Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity. Gastroenterology. 2008;134(4):1028–37. PubMed DOI

Nichols LA, et al. Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol. 2007;179(2):993–1003. PubMed DOI

Kyewski B, Immunology. A breath of Aire for the periphery. Science. 2008;321(5890):776–7. PubMed DOI

Liston A, et al. Aire regulates negative selection of organ-specific T cells. Nat Immunol. 2003;4(4):350–4. PubMed DOI

Miyazawa R, et al. Dispensable role of Aire in CD11c+ conventional dendritic cells for antigen presentation and shaping the transcriptome. Immunohorizons. 2023;7(1):140–58. PubMed DOI PMC

Link A, et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007;8(11):1255–65. PubMed DOI

Gardner JM, et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008;321(5890):843–7. PubMed DOI PMC

Gardner JM, et al. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4(+) T cells. Immunity. 2013;39(3):560–72. PubMed DOI PMC

Yamano T, et al. Aire-expressing ILC3-like cells in the lymph node display potent APC features. J Exp Med. 2019;216(5):1027–37. PubMed DOI PMC

Aschenbrenner K, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8(4):351–8. PubMed DOI

Dobes J, et al. Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans. Nat Immunol. 2022;23(7):1098–108. PubMed DOI

Wolff AS, et al. Flow cytometry study of blood cell subtypes reflects autoimmune and inflammatory processes in autoimmune polyendocrine syndrome type I. Scand J Immunol. 2010;71(6):459–67. PubMed DOI

Metzger TC, et al. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep. 2013;5(1):166–79. PubMed DOI

Gillis-Buck E, et al. Extrathymic Aire-expressing cells support maternal-fetal tolerance. Sci Immunol. 2021;6(61):eabf1968. PubMed DOI PMC

Wang J, et al. Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium. Sci Immunol. 2021;6(65):eabl5053. PubMed DOI PMC

Akagbosu B, et al. Novel antigen-presenting cell imparts T(reg)-dependent tolerance to gut microbiota. Nature. 2022;610(7933):752–60. PubMed DOI PMC

Lyu M, et al. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature. 2022;610(7933):744–51. PubMed DOI PMC

Kedmi R, et al. A RORgammat(+) cell instructs gut microbiota-specific T(reg) cell differentiation. Nature. 2022;610(7933):737–43. PubMed DOI PMC

Schlenner SM, et al. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity. 2010;32(3):426–36. PubMed DOI

Abramson J, et al. The emerging family of RORgammat(+) antigen-presenting cells. Nat Rev Immunol. 2023;24:64. PubMed DOI

Michelson DA, et al. Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. Cell. 2022;185(14):2542–2558 e18. PubMed DOI PMC

Dobes J, et al. A novel conditional Aire allele enables cell-specific ablation of the immune tolerance regulator Aire. Eur J Immunol. 2018;48(3):546–8. PubMed DOI

Kekalainen E, et al. Autoimmunity, not a developmental defect, is the cause for subfertility of autoimmune regulator (Aire) deficient mice. Scand J Immunol. 2015;81(5):298–304. PubMed DOI

Radhakrishnan K, et al. Autoimmune regulator (AIRE) is expressed in spermatogenic cells, and it altered the expression of several nucleic-acid-binding and cytoskeletal proteins in germ cell 1 spermatogonial (GC1-spg) cells. Mol Cell Proteomics. 2016;15(8):2686–98. PubMed DOI PMC

Petrusova J, Manning J, Filipp D. AIRE in male fertility: a new hypothesis. Cells. 2022;11(19):3168. PubMed DOI PMC

Nishikawa Y, et al. Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J Exp Med. 2010;207(5):963–71. PubMed DOI PMC

Gu B, et al. Aire regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells. Biochem Biophys Res Commun. 2010;394(2):418–23. PubMed DOI PMC

Bin G, et al. Aire promotes the self-renewal of embryonic stem cells through Lin28. Stem Cells Dev. 2012;21(15):2878–90. PubMed DOI PMC

Gu B, et al. AIRE is a critical spindle-associated protein in embryonic stem cells. elife. 2017;6:6. DOI

Matsumoto M, et al. Which model better fits the role of Aire in the establishment of self-tolerance: the transcription model or the maturation model? Front Immunol. 2013;4:210. PubMed DOI PMC

Nguyen CTK, et al. AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression. PLoS One. 2020;15(2):e0222689. PubMed DOI PMC

van Laar GG, van Hamburg JP, Tas SW. Extrathymic AIRE-expressing cells: friends or foes in autoimmunity and cancer? Autoimmun Rev. 2022;21(9):103141. PubMed DOI

Koh AS, et al. Rapid chromatin repression by Aire provides precise control of immune tolerance. Nat Immunol. 2018;19(2):162–72. PubMed DOI PMC

Hirano Y, et al. Structure of a cell polarity regulator, a complex between atypical PKC and Par6 PB1 domains. J Biol Chem. 2005;280(10):9653–61. PubMed DOI

Derbinski J, et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med. 2005;202(1):33–45. PubMed DOI PMC

Giraud M, et al. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci U S A. 2012;109(2):535–40. PubMed DOI

Org T, et al. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum Mol Genet. 2009;18(24):4699–710. PubMed DOI PMC

Nishijima H, et al. Ectopic Aire expression in the thymic cortex reveals inherent properties of Aire as a tolerogenic factor within the medulla. J Immunol. 2015;195(10):4641–9. PubMed DOI

Guerau-de-Arellano M, Mathis D, Benoist C. Transcriptional impact of Aire varies with cell type. Proc Natl Acad Sci U S A. 2008;105(37):14011–6. PubMed DOI PMC