Mechanisms of allergy and clinical immunology
Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen-specific T-cell tolerance in human tonsils and peripheral blood

https://doi.org/10.1016/j.jaci.2012.10.051Get rights and content

Background

The generation and maintenance of allergen-specific T-cell tolerance is a key step in healthy immune responses to allergens and successful allergen-specific immunotherapy. Breaking of peripheral T-cell tolerance to allergens can lead to the development of allergies, but the mechanisms are not completely understood.

Objective

We sought to identify molecular mechanisms that break allergen-specific T-cell tolerance in human subjects.

Methods

Proliferative responses of allergen-specific T cells from tonsils and peripheral blood were measured by using tritiated thymidine incorporation and carboxyfluorescein succinimidyl ester (CFSE) dilution experiments. Cytokine levels in cell-free supernatants were quantified by using the cytometric bead array, and mRNA expression of transcription factors and cytokines was determined by using quantitative PCR. Myeloid dendritic cells (DCs) were characterized by using flow cytometry.

Results

In allergic patients the immune profile of the tonsils represents the atopic status of patients, with low expression of the TH1 cell-specific transcription factor T-bet and the cytokine IFN-γ, as well as IL-10. Human tonsils show very low levels of allergen-induced T-cell proliferation, thus representing a very suitable in vivo model to assess mechanisms of breaking allergen-specific T-cell tolerance. Triggering of Toll-like receptor (TLR) 4 or TLR8 and the proinflammatory cytokines IL-1β or IL-6 break allergen-specific T-cell tolerance in human tonsils and peripheral blood through a mechanism dependent on the adaptor molecule myeloid differentiation primary response gene (88) (MyD88). In particular, myeloid DCs and stimulations that activate them broke the tolerance of allergen-specific CD4+ T cells, whereas plasmacytoid DCs and stimulations that activate them, such as TLR7 and TLR9, did not have any effect. Tolerance-breaking conditions induced by different molecular mechanisms were associated with a mixed cytokine profile with a tendency toward increased levels of IL-13 and IL-17, which are TH2 and TH17 cytokines, respectively.

Conclusion

Certain innate immune response signals and proinflammatory cytokines break allergen-specific CD4+ T-cell tolerance in normally unresponsive subjects, which might lead to the development or exacerbation of allergic diseases after encountering microbes or inflammatory conditions.

Section snippets

Study group

The study has been reviewed and approved by the ethics committees of the Cantons of Graubünden and Zürich and Satakunta Central Hospital, Pori, Finland. Heparinized peripheral blood samples from well-characterized nonallergic healthy and allergic donors were used in the study. Healthy buffy coats obtained from the Red Cross, Zurich, Switzerland, were used to optimize experimental conditions and general experiments with purified DC subsets. Noninflamed tonsils from patients undergoing

Characterization of the polyallergic atopic status in human palatine tonsils

To study mechanisms of breaking allergen-specific T-cell tolerance in human tonsils, we first analyzed whether these tissues reflect the classical features of allergic diseases at the T-cell level. Therefore we compared the mRNA expression levels of T-cell lineage–related cytokines and transcription factors in tonsillar tissues directly excised from a randomly selected population of 24 polyallergic atopic and 24 nonallergic control subjects. Experiments were performed without any stimulation to

Discussion

Our results show that tonsils are organs in which regulation of immune responses to allergens take place that show an essential difference in atopic patients, thus representing a very suitable in vivo model to assess mechanisms of breaking allergen-specific T-cell tolerance. We demonstrate how peripheral T-cell tolerance to major environmental allergens can be broken by triggering of TLR4 or TLR8 and by the proinflammatory cytokines IL-1β or IL-6 in human tonsils and peripheral blood. We also

References (49)

  • H.H. Oberg et al.

    Regulation of T cell activation by TLR ligands

    Eur J Cell Biol

    (2011)
  • J.A. Hirota et al.

    The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter

    J Allergy Clin Immunol

    (2012)
  • E.J. Wehrens et al.

    Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells

    Blood

    (2011)
  • T. Kawai et al.

    Toll-like receptors and their crosstalk with other innate receptors in infection and immunity

    Immunity

    (2011)
  • M. Wills-Karp

    Allergen-specific pattern recognition receptor pathways

    Curr Opin Immunol

    (2010)
  • S.J. Galli et al.

    The development of allergic inflammation

    Nature

    (2008)
  • C.A. Akdis et al.

    Mechanisms of allergen-specific immunotherapy

    J Allergy Clin Immunol

    (2011)
  • M. Jutel et al.

    IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy

    Eur J Immunol

    (2003)
  • V. Verhasselt et al.

    Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma

    Nat Med

    (2008)
  • M. Akdis et al.

    IgE class switching and cellular memory

    Nat Immunol

    (2012)
  • C. Ebner et al.

    Nonallergic individuals recognize the same T cell epitopes of Bet v 1, the major birch pollen allergen, as atopic patients

    J Immunol

    (1995)
  • M. Akdis et al.

    Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells

    J Exp Med

    (2004)
  • F. Meiler et al.

    In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure

    J Exp Med

    (2008)
  • M.R. Karlsson et al.

    Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy

    J Exp Med

    (2004)
  • Cited by (77)

    • Loss of regulatory capacity in Treg cells following rhinovirus infection

      2021, Journal of Allergy and Clinical Immunology
      Citation Excerpt :

      An important factor to be considered is the breaking of tolerance by RV-induced proinflammatory factors. We had previously reported that proinflammatory cytokines and TLR stimulation may break immune tolerance in T cells.58 Thus far unidentified mechanisms that break tolerance can also be activated by RV infection.

    • Plasmacytoid dendritic cells drive acute asthma exacerbations

      2018, Journal of Allergy and Clinical Immunology
    • Mechanisms of food allergy

      2018, Journal of Allergy and Clinical Immunology
      Citation Excerpt :

      One likely mechanism inducing desensitization, which to date has only been demonstrated in mice, is targeting of FcγRIIb on the surfaces of mast cells by IgG antibodies cross-linked by allergens.69-71 Several different molecular mechanisms have been suggested to play a role in the breaking of allergen tolerance, such as viral infections and proinflammatory cytokines, and triggering of receptors, such as rhinovirus infections, IL-1β and IL-6, and Toll-like receptor 4 and Toll-like receptor 8.72-74 In addition, the remission state can be dependent on the dose of exposed food allergen; although low doses are tolerated, high doses can trigger allergic symptoms.

    View all citing articles on Scopus

    Supported by Swiss National Foundation grants 32-125249 and 320030-132899, the Christine Kühne-Center for Allergy Research and Education (CK-CARE), European 7th frame work projects MeDALL: Mechanisms of the Development of Allergy (no. 261357), and PREDICTA: Post-Infectious Immune Reprogramming and Its Association with Persistence and Chronicity of Respiratory Allergic Diseases (no. 260895). U.C.K. was funded by a European Respiratory Society (ERS) Long Term Research Fellowship (no. 288), and O.P. is a Ramon y Cajal Scholar funded by MINECO and the European Social Fund. U.C.K. is supported by University of Istanbul, Research Fund (no. 2826).

    Disclosure of potential conflict of interest: T. Jartti has received research support from the Academy of Finland and Sigrid Juselius Foundation. C. A. Akdis has received research support from Novartis, PREDICTA, the Swiss National Science Foundation, MeDALL, the Global Allergy and Asthma European Network, and the Christine Kühne-Center for Allergy Research and Education; has provided consultation for Actellion, Aventis, Stallergenes, and Allergopharma; is president of the European Academy of Allergy and Clinical Immunology; is a fellow and interest group member for the American Academy of Allergy, Asthma & Immunology; is a former committee member of the Global Allergy and Asthma European Network; and is director of the Christine Kühne-Center for Allergy Research and Education. M. Akdis has received research support from the Swiss National Science Foundation, Predicta, and MeDALL. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

    View full text