title: Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing γδ T Cells to Promote Immunologic Tolerance.
abstract: Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector T cells and positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A+Vγ6+Vδ1+T cells, considered to be "early responders" to tissue stress and drivers of inflammatory reactions. Aire-dependent control of Il7 expression in mTECs regulated the size of thymic IL-17A+Vγ6+Vδ1+compartments. In mice lacking Aire and γδ T cells, certain tissues typically targeted in the "Aire-less" disease, notably the retina, were only minimally infiltrated. IL-17A+Vγ6+Vδ1+cells were present in the retina of wild-type mice and expanded very early in Aire-deficient mice. A putatively parallel population of IL-17A+Vγ9+Vδ2+T cells was increased in humans lacking Aire. Thus, Aire exerts multi-faceted autoimmune control that extends to a population of innate-like T cells.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Fujikado
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Mann
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kushagra
authors.initials: K
authors.lastname: Bansal
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, MD 20892, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Romito
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Elise M N
authors.initials: EMN
authors.lastname: Ferre
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, MD 20892, USA.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cb@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dm@hms.harvard.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D016133:Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology*; D059467:Transcriptome; D055815:Young Adult; D000096927:AIRE Protein
chemical_list: D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014157:Transcription Factors; D000096927:AIRE Protein