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

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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, [3H]-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+CD127FOXP3+ 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.

Section snippets

Tonsil samples

This study has been reviewed and approved by the ethic committee of Cantons of Graubünden and Zurich. Human palatine tonsils were obtained from the hospitals of Davos and Chur, Switzerland. Noninflammed tonsils from patients undergoing tonsillectomy were included in the study. Tonsil samples from atopic donors were compared with those from healthy individuals. Atopic patients showed a polyallergic status according to self-reported allergies to different pollen and foods. All atopic individuals

High numbers of functional CD4+FOXP3+ Treg cells in human palatine tonsils

The cell composition of TMCs showed a major difference in comparison with that of peripheral blood. The percentage of B cells in palatine TMCs was approximately 6 times higher than that of PBMCs, and the percentage of total T cells as well as the CD4+ and CD8+ T-cell compartments was significantly lower in TMCs (Fig 1, A). Although the frequency of T cells in tonsils was lower than in peripheral blood, the percentage of CD3+FOXP3+ and CD4+FOXP3+ Treg cells in TMCs was significantly high (Fig 1,

Discussion

The present study shows that oral tolerance to common allergens through the generation of allergen-specific Treg cells is taking place in human tonsils and suggests a suitable lymphatic organ for direct immune interventions for the treatment of allergic diseases and other immune tolerance–related disorders. Because of their anatomical localization with unique structural and functional features, tonsils mount innate and adaptive immune responses that must discriminate between potentially

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    The authors’ laboratories are supported by Swiss National Foundation grants 32-125249 and 320030-132899 and Christine Kühne-Center for Allergy Research and Education (CK-CARE). O.P. was supported by a postdoctoral fellowship from Ministerio de Educación y Ciencia and FECYT (Spain) and W.W.K by NIH contract HHSN272200700046C.

    This work was supported by the European Commission's Seventh Framework Programme under grant agreement no. 261357.

    Disclosure of potential conflict of interest: M. Akdis has received research support from the Swiss National Foundation, European Commission FP7 (MeDALL), and Predicta. C. A. Akdis has received research support from Novartis, Stallergenes, the Swiss National Science Foundation, Global Allergy and Asthma European Network, and Christine Kühne-Center for Allergy Research and Education; is a Fellow and interest group member of the American Academy of Allergy, Asthma & Immunology; is Vice President of the European Academy of Allergy and Clinical Immunology; and was a committee member for GA2LEN. The rest of the authors declare that they have no relevant conflicts of interest.

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