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Cell. 2016 Nov 3;167(4):1067-1078.e16. doi: 10.1016/j.cell.2016.09.050. Epub 2016 Oct 20.

Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans.

Author information

1
Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, 10117 Berlin, Germany.
2
German Rheumatism Research Centre (DRFZ) Berlin, Leibniz Association, 10117 Berlin, Germany.
3
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.
4
Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, 44625 Herne, Germany.
5
Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
6
Berlin-Brandenburg Center for Regenerative Therapies, Institute of Medical Immunology, Charité - University Medicine Berlin, 13353 Berlin, Germany.
7
Department of Pediatric Pneumology and Immunology, Cystic Fibrosis Centre Berlin, Charité - University Medicine Berlin, 13353 Berlin, Germany.
8
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, 10117 Berlin, Germany.
9
Department of Dermatology and Allergy, Allergy Center Charité, Charité - University Medicine Berlin, 10117 Berlin, Germany.
10
Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
11
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.
12
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.

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.

KEYWORDS:

CD137 (4-1BB); CD154 (CD40L); allergen; allergy; antigen-specific T cell; aspergillus fumigatus; birch pollen; regulatory T cell; tolerance; treg

PMID:
27773482
DOI:
10.1016/j.cell.2016.09.050
[Indexed for MEDLINE]
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