IL-35 production by inducible costimulator (ICOS)–positive regulatory T cells reverses established IL-17–dependent allergic airways disease Gregory S.

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IL-35 production by inducible costimulator (ICOS)–positive regulatory T cells reverses established IL-17–dependent allergic airways disease Gregory S. Whitehead, MSc, Rhonda H. Wilson, PhD, Keiko Nakano, BSc, Lauranell H. Burch, PhD, Hideki Nakano, PhD, Donald N. Cook, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 1, Pages 207-215.e5 (January 2012) DOI: 10.1016/j.jaci.2011.08.009 Copyright © 2011 Terms and Conditions

Fig 1 Prolonged allergen challenge suppresses allergic responses. A, Timeline. B, AHR in sensitized mice after various challenges. MCH, Methacholine. C, Leukocytes ± SEM in bronchoalveolar lavage fluid. D, Mean ± SEM cytokine levels in bronchoalveolar lavage fluid. E, Levels of IL-13 in homogenized lungs (n = 9 mice/group). ∗P < .05. Data represent one of 3 similar experiments. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig 2 Suppression of AHR is not due to loss of TH17 cells. A and B, Flow cytometric plots showing lymphocyte and CD4+ T-cell gating (Fig 2, A) and intracellular IL-17 staining (Fig 2, B). FSC, Forward scatter; SSC, side scatter. C and D, Percentage and number of TH17 cells per lung. E, Intracellular levels of IL-17 (mean fluorescent intensity [MFI]). Mean values ± SEM are shown. ∗P < .05 (n = 5 mice/group). Data represent one of 3 similar experiments. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig 3 Foxp3+ Treg cells suppress TH17-dependent allergic responses. A, Staining of IL-10 and Foxp3 in CD4+ T cells. B, Foxp3+ Treg cells per lung after the indicated number of OVA challenges and days of rest after challenge. C and D, Foxp3+ Treg cells in lungs of DTX-treated WT and DTR mice. E and F, Inflammation (Fig 3, E) and AHR (Fig 3, F) in 7-day OVA-challenged, DTX-treated mice. eos, Eosinophils; lym, lymphocytes; MCH, methacholine; neut, neutrophils. G, Dose-dependent Treg cell suppression of IL-17 secretion in vitro. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig 4 Suppression of AHR associates with increased ICOS+ Treg cell numbers. A, Staining of Foxp3+ Treg cells with isotype control antibodies (shaded region) or anti-ICOS antibodies after a single challenge (dashed line) or a 7-day challenge (solid line). B, Ratio of ICOS+ to ICOS− Treg cells after the indicated number of challenges and days of rest after challenge. C and D, Total Treg cells per lung (Fig 5, C) and ICOS+ Treg cells per lung (Fig 5, D) of WT and B7h−/− mice. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig 5 ICOS-B7h interactions suppress AHR. A-C, Allergic responses, including cytokines (Fig 5, A), leukocytes in bronchoalveolar lavage fluid (Fig 5, B) and AHR (Fig 5, C) in WT mice (open rectangles) and B7h−/− mice (solid rectangles) after a single OVA challenge. D-F, Allergic responses of the same strains after a 7-day OVA challenge. G, Total TH17 cell numbers in lungs of WT and B7h−/− mice. Eos, Eosinophils; Lym, lymphocytes; Mac, macrophages; Neut, neutrophils. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig 6 Suppression of AHR is independent of IL-10 and TGF-β but dependent on IL-35. A-C, Allergic responses to 7-day OVA challenge of IL-10–deficient mice (Fig 6, A), WT mice treated with anti–TGF-β antibodies (Fig 6, B), or Ebi-3−/− mice (Fig 6, C). D, Single OVA challenge of Ebi-3−/− mice. ∗P < .05 (n = 8 mice/group). eos, Eosinophils; lym, lymphocytes; mac, macrophages; neut, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig 7 IL-35 is selectively produced by ICOS+ Treg cells. Quantitative PCR was used to measure mRNA levels of each of the IL-35 and IL-27 subunits after flow cytometric sorting of Foxp3-gfp+ Treg cells into their ICOS+ and ICOS− fractions (n = 6). ∗P < .05. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig E1 Response to multiple OVA challenges depends on route of sensitization. A, Representative Alcian blue/periodic acid–Schiff staining of mucus-producing cells in OVA-LPS–sensitized murine lungs. B and C, AHR. Mice were sensitized and challenged as indicated. Mean ± SEM values are shown. ∗P < .05. Data represent one of 3 similar experiments (n = 9; Fig E1, B) or a single experiment (n = 6 mice/group; Fig E1, C). Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig E2 ICOS is required for the suppression of AHR. WT C57BL/6 and Icos−/− mice were sensitized to OVA-LPS through the airways and then challenged with aerosolized OVA on 7 consecutive days. Shown are the indicated leukocyte subsets, as well as AHR. Data represent mean ± SEM values from a single experiment. ∗P < .05 (n = 8 mice/group). eos, Eosinophils; lym, lymphocytes; mac, macrophages; neut, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig E3 Inhibiting TGF-β receptor signaling does not prevent suppression of AHR. Sensitized C57BL/6 mice were challenged and then given an inhibitor of TGF-β receptor signaling (SB-431542, Tocris Bioscience) on 3 consecutive days before harvest. Data presented are mean ± SEM values from one of 2 experiments producing similar results. ∗P < .05 (n = 8 mice/group). DMSO, Dimethyl sulfoxide. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions

Fig E4 IL-12p35 is required for suppression of AHR. C57BL/6 and p35-deficient mice were sensitized and then challenged with aerosolized OVA. A, Single OVA challenge. B, Seven daily OVA challenges. Mean ± SEM values are shown for the indicated leukocyte subsets and cytokines. Data represent one of 2 similar experiments. ∗P < .05 (n = 8 mice/group). eos, Eosinophils; lym, lymphocytes; mac, macrophages; neut, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 207-215.e5DOI: (10.1016/j.jaci.2011.08.009) Copyright © 2011 Terms and Conditions