title: Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans.
abstract: FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy.
authors: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, 10117 Berlin, Germany.
authors: Petra
authors: P
authors: Bacher
authors: German Rheumatism Research Centre (DRFZ) Berlin, Leibniz Association, 10117 Berlin, Germany.
authors: Frederik
authors: F
authors: Heinrich
authors: Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, 44625 Herne, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Institute of Medical Immunology, Charité - University Medicine Berlin, 13353 Berlin, Germany.
authors: Ulrik
authors: U
authors: Stervbo
authors: Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, 44625 Herne, Germany.
authors: Mikalai
authors: M
authors: Nienen
authors: Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
authors: Marco
authors: M
authors: Vahldieck
authors: Berlin-Brandenburg Center for Regenerative Therapies, Institute of Medical Immunology, Charité - University Medicine Berlin, 13353 Berlin, Germany.
authors: Christina
authors: C
authors: Iwert
authors: Berlin-Brandenburg Center for Regenerative Therapies, Institute of Medical Immunology, Charité - University Medicine Berlin, 13353 Berlin, Germany.
authors: Katrin
authors: K
authors: Vogt
authors: Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
authors: Jutta
authors: J
authors: Kollet
authors: Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, 44625 Herne, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Institute of Medical Immunology, Charité - University Medicine Berlin, 13353 Berlin, Germany.
authors: Nina
authors: N
authors: Babel
authors: Berlin-Brandenburg Center for Regenerative Therapies, Institute of Medical Immunology, Charité - University Medicine Berlin, 13353 Berlin, Germany.
authors: Birgit
authors: B
authors: Sawitzki
authors: Department of Pediatric Pneumology and Immunology, Cystic Fibrosis Centre Berlin, Charité - University Medicine Berlin, 13353 Berlin, Germany.
authors: Carsten
authors: C
authors: Schwarz
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, 10117 Berlin, Germany.
authors: Stefan
authors: S
authors: Bereswill
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, 10117 Berlin, Germany.
authors: Markus M
authors: MM
authors: Heimesaat
authors: Department of Dermatology and Allergy, Allergy Center Charité, Charité - University Medicine Berlin, 10117 Berlin, Germany.
authors: Guido
authors: G
authors: Heine
authors: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Gabriele
authors: G
authors: Gadermaier
authors: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Claudia
authors: C
authors: Asam
authors: Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
authors: Mario
authors: M
authors: Assenmacher
authors: 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, 07745 Jena, Germany.
authors: Olaf
authors: O
authors: Kniemeyer
authors: 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, 07745 Jena, Germany.
authors: Axel A
authors: AA
authors: Brakhage
authors: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Fátima
authors: F
authors: Ferreira
authors: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors: Michael
authors: M
authors: Wallner
authors: Department of Dermatology and Allergy, Allergy Center Charité, Charité - University Medicine Berlin, 10117 Berlin, Germany.
authors: Margitta
authors: M
authors: Worm
authors: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, 10117 Berlin, Germany; German Rheumatism Research Centre (DRFZ) Berlin, Leibniz Association, 10117 Berlin, Germany. Electronic address: alexander.scheffold@charite.de.
authors: Alexander
authors: A
authors: Scheffold
mesh_terms: D000485:Allergens / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000485:Allergens; D001324:Autoantigens
keywords: CD137 (4-1BB); CD154 (CD40L); allergen; allergy; antigen-specific T cell; aspergillus fumigatus; birch pollen; regulatory T cell; tolerance; treg