Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation Md Ashik Ullah, MPharm, Joana A. Revez,

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Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation Md Ashik Ullah, MPharm, Joana A. Revez, BSci, Zhixuan Loh, B Biomed Sci, Jennifer Simpson, B Biomed Sci, Vivian Zhang, PhD, Lisa Bain, BSci, Antiopi Varelias, PhD, Stefan Rose-John, PhD, Antje Blumenthal, PhD, Mark J. Smyth, PhD, Geoffrey R. Hill, MD, Maria B. Sukkar, PhD, Manuel A.R. Ferreira, PhD, Simon Phipps, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 4, Pages 1065-1073 (October 2015) DOI: 10.1016/j.jaci.2015.02.032 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Study design. CR, Cockroach; IgG, isotype IgG control antibody; MR16-1, anti–IL-6R mAb; sgp130Fc, soluble gp130 fusion protein. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-6R inhibition attenuated cockroach (CR)–induced, but not HDM-induced, airway inflammation. Effect of IL-6R inhibition (anti–IL-6R; 1 mg) in HDM-induced (A-C) and cockroach-induced (D-E) airway inflammation is shown. BALF differential counts are shown in Fig 2, A and D. BALF chemokine (Fig 2, B and E) and cytokine (Fig 2, C and F) expression is also shown. There were 5 to 6 mice in the PBS and 8 to 12 mice in the allergen-challenged groups. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophages; Neu, neutrophils. *P < .05, **P < .01, and ***P < .001 versus PBS. §P < .05 and §§P < .01 versus cockroach plus IgG. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 LPS/TLR4 signaling contributes to allergen-induced IL-6 production. A, IL-6 expression in BALF of allergen-challenged WT mice (n = 6-9 mice). **P < .01 and ***P < .001 versus PBS. §P < .05 versus cockroach. B, IL-6 production by allergen-stimulated splenocytes. C, IL-6 expression in BALF of allergen-challenged WT and TLR4−/− mice (n = 4-6 mice). *P < .05, **P < .01, and ***P < .001 versus PBS or media. §P < .05 versus WT. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Cockroach (CR), but not HDM, induced sIL-6R expression through TLR2 activation. A, Allergen-induced sIL-6R expression in WT mice (n = 4-8 mice). **P < .01 versus PBS. §§§P < .001 versus cockroach. B-D, sIL-6R expression in splenocytes cultures (n = 3-7 mice). *P < .05, **P < .01, and ***P < .001 versus PBS or media. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Selective inhibition of IL-6 trans-signaling attenuated cockroach (CR)–induced airway inflammation. Mice were treated with 250 μg of soluble gp130-Fc 24 hours before challenge. A, BALF differential count. B, BALF chemokine expression. C, BALF cytokine expression. There were 6 to 9 mice in each group. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophages; Neu, neutrophils. §P < .05 and §§P < .01 versus cockroach plus PBS. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 γδ T cells are the major producers of IL-17A after cockroach (CR) challenge. A, Representative flow cytometric plots showing IL-17A–producing cells in response to cockroach challenge. FSC, Forward scatter. B, Number of different IL-17A–producing cells in the lung and enhanced yellow fluorescent protein (eYFP) expression presented as median fluorescence intensity (MFI). NK, Natural killer. There were 3 mice in each group. *P < .05, **P < .01, and ***P < .001 versus PBS. §P < .05 and §§§P < .001 versus cockroach plus IgG. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Airway immune response triggered by cockroach (CR) challenge was attenuated in TCRδ−/− mice. A, BALF differential count. B-D, BALF chemokines (Fig 7, B and C) and sIL-6R (Fig 7, D) expression in WT and TCRδ−/− mice. There were 5 to 8 mice per group. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophages; Neu, neutrophils. *P < .05, **P < .01, and ***P < .001 versus PBS. §P < .05, §§P < .01, and §§§P < .001 versus WT cockroach. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 IL-6 and sIL-6R protein levels in induced sputum samples from 33 patients with mild-to-moderate asthma. A, Correlation between IL-6 and sIL-6R levels. Circle colors indicate sputum inflammatory subtypes, whereas vertical and horizontal black lines show overall median sIL-6R and IL-6 levels, respectively. B, Proportion of subjects with both high (greater than median) sputum IL-6 and high sputum sIL-6R levels. Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E10 Journal of Allergy and Clinical Immunology 2015 136, 1065-1073DOI: (10.1016/j.jaci.2015.02.032) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions