Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33 Amit K. Mehta,

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Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33 Amit K. Mehta, PhD, Wei Duan, PhD, Astrid M. Doerner, PhD, Suzanne L. Traves, PhD, David H. Broide, MB, ChB, David Proud, PhD, Bruce L. Zuraw, MD, Michael Croft, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 1, Pages 278-288.e6 (January 2016) DOI: 10.1016/j.jaci.2015.05.007 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Rhinovirus blocks induction of tolerance to inhaled antigen. A, Schematic of experimental protocols. Mice were tolerized with intranasal OVA with or without RV1B. Nontolerized mice received PBS intranasally. All mice were sensitized with OVA/alum intraperitoneally on day 10 and challenged with intranasal OVA 2 weeks later to assess lung inflammation. B-D, BAL eosinophils, neutrophils, and lymphocytes. E, Hematoxylin and eosin–stained lung sections (upper) and inflammation scores (lower). F and G, IL-5 and IL-13 in BALF (upper) and LN culture supernatant (lower). H, BAL eosinophils and neutrophils in mice given intranasal OVA with rhinovirus that were not challenged or challenged with OVA. Results are means ± SEMs from 4 mice per group and representative of 3 experiments. i.n., Intranasal; i.p., intraperitoneal; ND, not determined; RV, rhinovirus. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Rhinovirus infection inhibits airway tolerance through OX40L. A, OX40L mRNA in lung tissue after RV1B infection. B, OX40L on CD11c+ cells: isotype control (solid gray area), naive (dashed line), and RV1B (solid black line). C-F, Wild-type mice were tolerized, sensitized, and challenged as in Fig 1, A. Anti-OX40L or control antibody was administered intraperitoneally at the time of RV1B infection. Fig 2, C and D, BAL eosinophils and neutrophils. Fig 2, E, Hematoxylin and eosin–stained lung sections (left) and inflammation scores (right). Fig 2, F, BALF IL-5 and IL-13. Results are means ± SEMs from 3 to 4 mice per group and representative of 3 experiments. i.n., Intranasal; ND, not determined; RV, rhinovirus. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Rhinovirus suppresses generation of OVA-specific Foxp3+ T cells through OX40L. OVA-specific OT-II T cells were transferred into congenic mice that were then tolerized with OVA administered intranasally on 3 consecutive days with or without RV1B infection. Mice were treated with IgG or α-OX40L at the time of RV1B infection. A, Number of Foxp3+ OT-II T cells enumerated in LNs (left) and lung tissue (right) by means of flow cytometry 5 days after the first inhalation of soluble OVA. B and C, Number of IL-4– and IL-13–secreting CD4 T cells enumerated in LNs by using ELISPOT at the same time. D and E, Ratio of Foxp3+ and IL-4– and IL-13–secreting CD4 T cells. Results are means ± SEMs from 3 to 4 mice per group and representative of 2 experiments. i.n., Intranasal; RV, rhinovirus. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TSLP is required for rhinovirus to modulate the lung tolerogenic environment. A, TSLP mRNA in lung tissue after RV1B infection over 72 hours. B, TSLP protein in BALF after 24 hours. C, OX40L mRNA in lung tissue after RV1B infection of wild-type or TSLPR−/− mice at 5 hours. D-F, OT-II T cells were transferred into wild-type or TSLPR−/− mice, as in Fig 3. Recipients were tolerized with OVA and infected with RV1B as before. Fig 4, D, Number of Foxp3+ OT-II T cells in LNs 5 days after OVA inhalation. Fig 4, E, Number of IL-4–secreting CD4 T cells in LNs. Fig 4, F, Ratio of Foxp3+ and IL-4–secreting CD4 T cells in LNs. Results are means ± SEMs from 3 to 4 mice per group and representative of 2 experiments. i.n., Intranasal; ND, not determined; RV, rhinovirus; WT, wild-type. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IL-33 is necessary for rhinovirus to block airway tolerance. A, IL-33 mRNA in lung tissue after RV1B infection over 72 hours. B, IL-33 protein in BALF after 24 hours. C-H, Wild-type mice were tolerized, sensitized, and challenged as in Fig 1, A, to assess lung inflammation. Anti-T1/ST2 or control antibody was administered intraperitoneally at the time of RV1B infection. Fig 5, C-E, BAL eosinophils, neutrophils, and lymphocytes. Fig 5, F and G, IL-5 and IL-13 in BALF (upper) and LN culture supernatant (lower). Fig 5, H, Hematoxylin and eosin–stained lung sections (left) and inflammation score (right). Results are means ± SEMs from 4 mice per group and representative of 2 to 3 independent experiments. i.n., Intranasal; ND, not determined; RV, rhinovirus. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-33 is required for rhinovirus to modulate the Treg/TH2 balance. A, OX40L mRNA at 5 hours in lung tissue of control IgG- and α-T1/ST2–treated mice after RV1B infection. B-D, OT-II T cells were transferred into wild-type congenic mice, as in Fig 3. Recipients were tolerized and infected with RV1B as before. Fig 6, B, Number of Foxp3+ OT-II T cells enumerated in LNs by using flow cytometry 5 days after OVA inhalation. Fig 6, C, Number of IL-4–secreting CD4 T cells in LNs by using ELISPOT. Fig 6, D, Ratio of Foxp3+ to IL-4–secreting CD4 T cells. Results are means ± SEMs from 3 to 4 mice per group and representative of 2 independent experiments. i.n., Intranasal; RV, rhinovirus. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 TSLP and IL-33 are upregulated in human airway epithelial cells by rhinovirus. TSLP mRNA (A and B) and IL-33 mRNA (C and D) from 24 to 72 hours in NHBE cells and PBECs after RV16 infection in vitro compared with unstimulated controls (UN). Results are means ± SEMs from 3 independent experiments with cells from a single donor for NHBE cells and means ± SEM from cells derived from 3 different donors for PBECs. PBEC results are representative of 2 experiments. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Effect of rhinovirus infection after tolerization. Wild-type mice were administered soluble OVA intranasally on days −10 to −8 and infected with RV1B either at day −10 or day 0 and sensitized and challenged as described in Fig 1, A. A and B, BAL eosinophils and neutrophils. C and D, BALF and LN IL-5 levels. Results are means ± SEMs from 5 to 8 mice per group, and data were pooled from 2 independent experiments. i.n., Intranasal; ND, not determined; RV, rhinovirus. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Effect of OX40L antibody without tolerance. Wild-type mice were administered α-OX40L or control antibody without RV1B infection or soluble intranasal OVA but sensitized 10 days later and challenged as described in Fig 1, A. A, BAL eosinophils. B and C, IL-5 and IL-13 in BALF. Results are means ± SEMs from 6 to 7 mice per group, and data were pooled from 2 independent experiments. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 TSLP is required for rhinovirus to inhibit airway tolerance. Wild-type and TSLPR−/− mice were tolerized, sensitized, and challenged as in Fig 1, A, to assess lung inflammation. A-C, BAL eosinophils, neutrophils, and lymphocytes. D and E, IL-5 and IL-13, respectively, in BALF (upper) and LN culture supernatant (lower). F, Hematoxylin and eosin–stained lung sections (left) and inflammation score (right). Results are means ± SEMs from 4 mice per group and representative of 2 to 3 independent experiments. i.n., Intranasal; ND, not determined; RV, rhinovirus. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Effect of α-T1/ST2 antibody without tolerance. Wild-type mice were given α-T1/ST2 or control antibody without RV1B infection or soluble intranasal OVA but sensitized 10 days later and challenged as described in Fig 1, A. A and B, BAL eosinophils and neutrophils. Results are means ± SEMs from 6 to 7 mice per group, and data were pooled from 2 independent experiments. Journal of Allergy and Clinical Immunology 2016 137, 278-288.e6DOI: (10.1016/j.jaci.2015.05.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions