Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 2; pp. 510 - 520.e9
• Main Authors: Palomares, Oscar, PhD, Rückert, Beate, Jartti, Tuomas, MD, Kücüksezer, Umut Can, MD, PhD, Puhakka, Tuomo, MD, Gomez, Enrique, PhD, Fahrner, Heinz B., MD, Speiser, Andreas, MD, Jung, Andreas, MD, Kwok, William W., PhD, Kalogjera, Livije, MD, Akdis, Mübeccel, MD, PhD, Akdis, Cezmi A., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2012; Elsevier; Elsevier Limited
• Subjects: allergen-specific Treg cells; Allergens - immunology; Allergy and Immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Dendritic Cells - immunology; Forkhead Transcription Factors - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Histology; Humans; Immune system; Immune Tolerance; Immunopathology; Interleukin-3 - immunology; Lymphocytes; Medical sciences; myeloid dendritic cells; Palatine Tonsil - immunology; Peptides; plasmacytoid dendritic cells; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Studies; T cell receptors; T-Lymphocytes, Regulatory - immunology; Throat surgery; Toll-Like Receptors - immunology; tonsils; PC5; Tonsil mononuclear cells; allergen-specific Treg cells; Dendritic cells; TDCs; Treg; myeloid dendritic cells; CFSE; TMCs; tonsils; Tonsil dendritic cells; plasmacytoid dendritic cells; DCs; mDCs; Immune tolerance; pDCs; Regulatory T; Carboxy-fluorescein succinimidyl ester; TLR; Phycoerythrin and cyanin 5; Toll-like receptor; Human; Allergy; Dendritic cell; Immunopathology; Amygdala; Induction; Treg cell; Oral administration; Plasmacytoid dendritic cell; First line treatment; Immunology; Antigen presenting cell; Myeloid dendritic cell; Transcription factor FOXP3; Allergen; Organ
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.09.031

Background Tonsils are strategically located in the gateway of both alimentary and respiratory tracts representing the first contact point of food and aeroallergens with the immune system. Tonsillectomy removes only the palatine tonsils and sometimes adenoids. Lingual tonsil is anatomically big and remains lifelong intact. Objective The aim of this study was to demonstrate cellular and molecular mechanisms of oral tolerance induction to food and aeroallergens in human tonsils. Methods Tonsil allergen-specific FOXP3+ regulatory T (Treg) cells, plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells were characterized by flow cytometry and suppressive assays. Intracellular staining, [3 H]-thymidine incorporation, and carboxy-fluorescein succinimidyl ester dilution experiments were performed. Tonsil biopsies were analyzed by confocal microscopy. Results CD4+ FOXP3+ Treg cells and pDCs constitute important T- and dendritic cell–compartments in palatine and lingual tonsils. Tonsil pDCs have the ability to generate functional CD4+ CD25+ CD127− FOXP3+ Treg cells with suppressive property from naive T cells. CD4+ FOXP3+ Treg cells proliferate and colocalize with pDCs in vivo in T-cell areas of lingual and palatine tonsils. Tonsil T cells did not proliferate to common food and aeroallergens. Depletion of FOXP3+ Treg cells enables the allergen-induced proliferation of tonsil T cells, indicating an active role of Treg cells in allergen-specific T-cell unresponsiveness. High numbers of major birch pollen allergen, Bet v 1–specific CD4+ FOXP3+ Treg cells, are identified in human tonsils compared with peripheral blood. A positive correlation between the percentages of FOXP3+ Treg cells and pDCs is observed in tonsils from nonatopic individuals. Conclusion Functional allergen-specific Treg cells are identified both in lingual and in palatine tonsils.