title: Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against mucosal fungi.
abstract: Foxp3(+) regulatory T cells (Treg) have a central role for keeping the balance between pro- and anti-inflammatory immune responses against chronically encountered antigens at mucosal sites. However, their antigen specificity especially in humans is largely unknown. Here we used a sensitive enrichment technology for antigen-reactive T cells to directly compare the conventional vs. regulatory CD4(+) T-cell response directed against two ubiquitous mucosal fungi, Aspergillus fumigatus and Candida albicans. In healthy humans, fungus-specific CD4(+)CD25(+)CD127(-)Foxp3(+) Treg are strongly expanded in peripheral blood and possess phenotypic, epigenetic and functional features of thymus-derived Treg. Intriguingly, for A. fumigatus, the strong Treg response contrasts with minimal conventional T-cell memory, indicating selective Treg expansion as an effective mechanism to prevent inappropriate immune activation in healthy individuals. By contrast, in subjects with A. fumigatus allergies, specific Th2 cells were strongly expanded despite the presence of specific Treg. Taken together, we demonstrate a largely expanded Treg population specific for mucosal fungi as part of the physiological human T-cell repertoire and identify a unique capacity of A. fumigatus to selectively generate Treg responses as a potentially important mechanism for the prevention of allergic reactions.
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Bacher
authors.affiliation: 1] Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knoell Institute (HKI) Jena and Friedrich Schiller University Jena, Jena, Germany [2] Integrated Research and Treatment Center, Center for Sepsis Control and Care Jena, University Hospital (CSCC), Jena, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Kniemeyer
authors.affiliation: Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schönbrunn
authors.affiliation: Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Assenmacher
authors.affiliation: CF Centre Cologne, Children's Hospital, University of Cologne, Cologne, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Rietschel
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Steinbach
authors.affiliation: 1] Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany [2] Clinical Trials Center Cologne ZKS Köln (BMBF 01KN1106), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Integrated Oncology CIO Köln-Bonn, University of Cologne, Cologne, Germany.
authors.forename: O A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knoell Institute (HKI) Jena and Friedrich Schiller University Jena, Jena, Germany.
authors.forename: A A
authors.initials: AA
authors.lastname: Brakhage
authors.affiliation: Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Thiel
authors.affiliation: 1] Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany [2] German Rheumatism Research Centre (DRFZ) Berlin, Leibniz Association, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Scheffold
mesh_terms: D000946:Antigens, Fungal / Q000276:immunology*; D001230:Aspergillus / Q000276:immunology; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000150:complications / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005658:Fungi / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D007108:Immune Tolerance; D007156:Immunologic Memory; D016130:Immunophenotyping; D018655:Lymphocyte Count; D009092:Mucous Membrane / Q000276:immunology* / Q000382:microbiology*; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism
chemical_list: D000946:Antigens, Fungal; D018984:Epitopes, T-Lymphocyte; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9