Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator–inducible T-cell.

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Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator–inducible T-cell costimulator ligand interaction Diamanda Rigas, MS, Gavin Lewis, PhD, Jennifer L. Aron, MD, Bowen Wang, MS, Homayon Banie, BS, Ishwarya Sankaranarayanan, MS, Lauriane Galle-Treger, PhD, Hadi Maazi, DVM, PhD, Richard Lo, BS, Gordon J. Freeman, PhD, Arlene H. Sharpe, MD, PhD, Pejman Soroosh, PhD, Omid Akbari, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1468-1477.e2 (May 2017) DOI: 10.1016/j.jaci.2016.08.034 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 iTreg cells attenuate cytokine production. ILC2s from rIL-33–treated mice were cocultured for 48 hours with in vitro–induced iTreg cells (A), Teff cells (B), and natural thymic nTreg cells (C) from FoxP3GFP+ mice, after which IL-5 and IL-13 cytokine levels were measured with ELISA. Data are presented as means ± SEMs (n = 4). ***P < .001 and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 iTreg cells abrogate AHR induced by IL-33 or Alternaria species. A and D, Rag2−/− mice received PBS, IL-33, or Alternaria species extract and either iTreg cells or no Treg cells, according to schema. B, C, E, and F, AHR was assessed by measuring lung resistance (Fig 2, B and E), and BAL fluid eosinophil numbers were measured by using flow cytometry (Fig 2, C and F). Data are expressed as means ± SEMs (n = 5). *P < .05, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 iTreg cells suppress expression of type 2 cytokines by ILC2s. A, Fold change (log2; LogFC) of 270 mRNAs in ILC2s repurified after 48 hours of culture with iTreg cells. B, Significantly regulated genes (fold change < 2, P < .05). C, IL-5 and IL-13 production measured by means of ELISA in ILC2–iTreg cell cocultures with anti–TGF-β or anti–IL-10 neutralizing antibodies. D, LAP expression on iTreg and nTreg cells by using flow cytometry. Data are shown as means ± SEMs (n = 3). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 The suppressive effect of iTreg cells is mediated by inhibitory cytokines. ILC2s were cultured in the presence of 10 ng/mL rTGF-β1, rIL-10, or both. A and B, IL-5 and IL-13 production was measured by using ELISA. C and D, Cultured ILC2s were also assessed for the expression of 7-aminoactinomycin (7AAD)/Annexin V (AnnV) and Ki67 by using flow cytometry. Data are presented as means ± SEMs (n = 4). *P < .05, **P < .005, and ***P < .0005. NT, Non-treated. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 iTreg cell–mediated suppression of ILC2s requires ICOSL and is contact dependent. A, ILC2s were cocultured with iTreg cells with or without transwell membrane. B and C, In the presence or absence of ICOSL-neutralizing antibodies, iTreg cells were cocultured with wild-type ILC2s (Fig 5, B) or ICOS−/− ILC2s (Fig 5, C). After 48 hours, IL-5 and IL-13 levels were measured by using ELISA. Data are presented as means ± SEMs (n = 4). *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 ICOS-ICOSL interaction is required for suppression of human ILC2s by iTreg cells. Human CD4+ naive cells were induced into iTreg cells and then purified and cocultured with syngeneic ILC2s in the presence of either isotype or anti-ICOSL antibodies for 48 hours. Cytokine production determined by means of ELISA (A) and percentage of cytokine suppression are shown (B). Data are presented as means ± SEMs (n = 4). *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Suppression of syngeneic ILC2s by iTreg cells in humanized mice is dependent on ICOSL. A, Purified human ILC2s, human iTreg cells, or human Teff cells, alone or in homologous combination, were adoptively transferred to groups of NSG mice according to scheme. B, AHR and BAL fluid eosinophils were assessed by measuring lung resistance on day 3. C, AHR and BAL as in B, in mice treated with anti-ICOSL or isotype control. Data are expressed as means ± SEMs (n = 5). **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Flow cytometric gating strategies for isolation and sorting of murine ILC2s (A), human ILC2s (B), murine iTreg cells (C), and human iTreg cells (D), as described in the Methods section. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 ILC2s and iTreg cells were cocultured as described in Fig 1, A, in the presence of isotype or anti-ICOSL blocking antibody for 48 hours, after which the IL-10 level was quantified by means of ELISA (A), and the LAP level was measured by means of flow cytometry (B). MFI, Mean fluorescence intensity. Data are expressed as means ± SEMs (n = 5). **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1468-1477.e2DOI: (10.1016/j.jaci.2016.08.034) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions