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

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Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen- specific T-cell tolerance in human tonsils and peripheral blood Umut Can Kücüksezer, PhD, Oscar Palomares, PhD, Beate Rückert, Tuomas Jartti, MD, Tuomo Puhakka, MD, Andreas Nandy, PhD, Bilun Gemicioğlu, MD, PhD, Heinz B. Fahrner, MD, Andreas Jung, MD, Günnur Deniz, PhD, Cezmi A. Akdis, MD, Mübeccel Akdis, MD, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 3, Pages 875-885.e9 (March 2013) DOI: 10.1016/j.jaci.2012.10.051 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 In vivo mRNA expression levels of cytokines or T-cell transcription factors in tonsils. The mRNA expression in palatine tonsils of 24 atopic and 24 nonatopic subjects was determined by using quantitative real-time RT-PCR. The T-bet/GATA3 ratio is also shown. Arbitrary units (A.u.) are 2−(ΔCT) values multiplied by 104, with ΔCT defined as the difference between the cycle threshold value for the gene of interest and EF1α. **P < .01 and ***P < .001. Data represent means with SEMs. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TMCs from atopic and nonatopic subjects respond differently to allergen stimulation. A total of 8 TMCs from atopic (n = 4) and nonatopic (n = 4) subjects were stimulated with Phl p 5a and Bet v 1 for 5 days. Fold-increased mRNA expression of the indicated genes relative to the corresponding unstimulated condition is shown. Data represent means with SEMs. *P < .05. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TLR8 triggering breaks allergen-specific unresponsiveness in human TMCs. A, TMCs (n = 4) and PBMCs (n = 7) from atopic subjects and TMCs (n = 3) and PBMCs (n = 3) from nonatopic subjects were cultured alone (us) or with the indicated allergens. Data represent means with SEMs. *P < .05. B, Proliferation of CFSE-labeled CD4+ TMCs after 5 days of activation with the indicated stimulus. The mean percentage of proliferating cells of at least 2 independent experiments is shown. C, TMCs (n = 9) from 3 different donors were cultured with the indicated stimulus for 5 days. Proliferative responses were measured by using tritiated thymidine incorporation. Background of proliferation ranged between 102 and 460 cpm. Stim. Index, Stimulation index. **P < .01. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Triggering of TLR4 and TLR8 breaks peripheral allergen-specific CD4+ T-cell tolerance. A, Proliferation of CFSE-labeled CD4+ PBMCs after 5 days of stimulation with TLR4-L alone or in combination with Phl p 5a. B, Stimulation with TLR8-L alone or in combination with Bet v 1. One representative example of 4 with similar results is shown. The graphs show a minimum of 5 proliferative experiments by using tritiated thymidine incorporation. Background of proliferation was less than 2000 cpm. *P < .05. Stim. Index, Stimulation index. C, PBMCs (n = 5) were stimulated with the indicated stimulus for 5 days. IL-13, IFN-γ, IL-1β, and IL-17 levels in supernatants were quantified. *P < .05, **P < .01. Ag, Antigen; us, unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Stimulation with IL-1β or IL-6 breaks allergen-specific CD4+ T-cell tolerance. A, Proliferation of CFSE-labeled CD4+ PBMCs after 5 days of stimulation with IL-1β alone or in combination with Phl p 2. B, Stimulation with IL-6 alone or in combination with PLA2. One representative example of 4 with similar results. The graphs show 7 individual proliferative experiments using tritiated thymidine incorporation. Background of proliferation was less than 2000 cpm. *P < .05. C, Proliferative responses of PBMCs preincubated with a peptide inhibitor of MYD88 (Pep-MYD88) or the corresponding peptide control (Pep-Control) and stimulated as indicated were measured by using tritiated thymidine incorporation. The data represent the means with SEMs of 4 independent experiments. Stim. Index, Stimulation index. *P < .05. Ag, Antigen; us, unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 mDCs are potent in the breaking of peripheral allergen-specific CD4+ T-cell tolerance. A, Proliferation of CFSE-labeled CD4+ PBMCs from nonallergic but sensitized subjects after 5 days of stimulation with Bet v 1 alone or in the presence of an additional 2.5 × 104 purified autologous mDCs. One representative example of 4 with similar results. The graph shows 7 individual proliferative experiments using tritiated thymidine incorporation. *P < .05. B, The same type of experiments in the presence of an equivalent number of pDCs (n = 5). Stim. Index, Stimulation index. C, PBMCs (n = 5) were unstimulated as indicated for 5 days. IL-13, IFN-γ, IL-1β, and IL-17 levels in supernatants were quantified. *P < .05, **P < .01. Ag, Antigen; us, unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Cytokine profile of tonsillar T cells from atopic and nonatopic donors. A, TMCs from atopic (n = 4) and nonatopic (n = 4) subjects were stimulated with Phl p 5a or Bet v 1 for 5 days. B, Purified tonsillar CD4+ T cells from atopic (n = 4) and nonatopic (n = 4) subjects were stimulated with anti-CD2/CD3/CD28 for 24 hours. The levels of the shown cytokines in cell-free supernatants were quantified by using the cytometric bead array. All data are means with SEMs. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 TMC proliferation after stimulation with TLR-Ls. A, CFSE-labeled TMCs were stimulated with TLR7-L, TLR8-L, or TLR9-L or left unstimulated (us) for 5 days. Proliferating CD4+ T cells were visualized by using flow cytometry. One representative example of at least 5 experiments with similar results is displayed. B, Quantification of the percentage of proliferating CD4+ T cells referred to unstimulated conditions (n = 5). C, Proliferative responses were also measured by using tritiated thymidine incorporation (n = 6). Background proliferation of unstimulated cells was less than 965 cpm. Stim. Index, Stimulation index. us, unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Stimulation of PBMCs with TLR7-L or TLR9-L does not break allergen-specific T-cell tolerance. Results of proliferative experiments with PBMCs after stimulation with allergens alone (+Ag) or in combination with TLR7-L (n = 7) or TLR9-L (n = 9) for 5 days by using tritiated thymidine incorporation are shown. The graphs show stimulation indices (Stim. Index). Background proliferation of unstimulated cells was less than 2000 cpm. All data are means with SEMs. US, Unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Cytokine profile of PBMCs after allergen stimulation in the presence of IL-1β or IL-6. PBMCs were unstimulated or stimulated with allergens alone (+Ag), with IL-1β (n = 5) or IL-6 (n = 5) alone, or with the allergens in the presence of the indicated cytokines for 5 days. The IL-13, IFN-γ, IL-1β, and IL-17 levels in cell-free supernatants were quantified by using the cytometric bead array. *P < .05, **P < .01, ***P < .001. us, Unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Simultaneous activation of PBMCs with IL-1β and IL-6 induces nonspecific proliferation. IL-17 or IL-23 stimulation did not have tolerance-breaking effects. Proliferative experiments of PBMCs stimulated with allergens alone (+Ag) or in combination with IL-1β and IL-6 simultaneously (n = 4) or IL-17 (n = 4) or IL-23 (n = 4) for 5 days by using tritiated thymidine incorporation. The graphs show stimulation indices (Stim. Index). Background proliferation of unstimulated cells was less than 2000 cpm. All data are means with SEMs. US, Unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Role of MyD88 in breaking tolerance to allergens by IL-1β, TLR4-L, and TLR8-L. PBMCs were preincubated for 3 hours with a peptide inhibitor of MyD88 (Pepinh-MYD88) or with the corresponding peptide control (Pepinh-Control), washed, and stimulated with the indicated allergens alone; with IL-1β, TLR4-L, or TLR8-L alone; or with the allergens in the presence of the shown stimulus. Proliferative responses by tritiated thymidine incorporation of 4 independent experiments are shown. Stim. Index, Stimulation index. us, unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Characterization of mDCs breaking allergen-specific T-cell tolerance. A, Flow cytometric representative dot plots of HLA-DR/OX40L or DC-SIGN/CD80 in purified mDCs stimulated with IL-1β, IL-6, or TLR8-L for 48 hours. One representative example of 3 with similar results is shown. B, The mean fluorescence intensity ratio of HLA-DR/DC-SIGN and CD80/DC-SIGN in purified mDCs after 48 hours of activation with IL-1β, IL-6, or TLR8-L. All data are means with SEMs. us, Unstimulated. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 mDCs synergize with IL-1β or IL-6 to break allergen-specific T-cell tolerance. Representative dot plots for the proliferation of CFSE-labeled CD4+ PBMCs from a nonallergic subject sensitized to PLA2 after 5 days of stimulation with IL-1β, IL-6 or PLA2 allergen alone, IL-1β and PLA2 or IL-6 and PLA2. The same proliferation assay was also performed in the presence of additional purified autologous mDCs. Journal of Allergy and Clinical Immunology 2013 131, 875-885.e9DOI: (10.1016/j.jaci.2012.10.051) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions