Lung dendritic cells induce TH17 cells that produce TH2 cytokines, express GATA-3, and promote airway inflammation Marianne Raymond, PhD, Vu Quang Van,

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Lung dendritic cells induce TH17 cells that produce TH2 cytokines, express GATA-3, and promote airway inflammation Marianne Raymond, PhD, Vu Quang Van, PhD, Keiko Wakahara, MD, PhD, Manuel Rubio, BSc, Marika Sarfati, MD, PhD Journal of Allergy and Clinical Immunology Volume 128, Issue 1, Pages 192-201.e6 (July 2011) DOI: 10.1016/j.jaci.2011.04.029 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Repetitive local administration of OVA-DCs induces an IgE-independent antigen-specific TH17 response. Mice were injected with PBS-DCs or OVA-DCs intratracheally (IT) at days 0, 12, and 15. A, Lung sections stained with hematoxylin and eosin (H&E) and periodic acid–Schiff (PAS). B, Differential cell count in bronchoalveolar lavage fluid. C, Total IgE level in serum. D and E, Cytokine release by mLN cells after OVA restimulation in vitro (Fig 1, D) and lung explants (Fig 1, E). Values are presented as means ± SEMs (n = 4-8 mice per group from at least 2 independent experiments). ∗∗∗P < .001, ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Systemic injection of OVA-DCs induces antigen-specific TH17-associated airway inflammation. Mice were injected with PBS-DCs or OVA-DCs intravenously (IV) at days 0, 12, and 15. A, Lung sections stained with hematoxylin and eosin (H&E) and periodic acid–Schiff (PAS). B, Differential cell count in bronchoalveolar lavage fluid. C, Total IgE level in serum. D and E, Cytokine release by mLN cells after OVA restimulation in vitro (Fig 2, D) and lung explants (Fig 2, E). Values are presented as means ± SEMs (n = 4-7 mice per group from at least 2 independent experiments). ∗∗∗P < .001, ∗∗P < .01. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Local and systemic administration of inflammatory OVA-DCs induces double IL-17+IL-13+–producing T cells in mLNs. Mice were injected with PBS-DCs or OVA-DCs intratracheally (IT) or intravenously (IV) at days 0, 12, and 15. A, IL-17 and IL-13 expression of CD4+ T cells in mLNs. B, IL-17+IL-13+–producing CD4+ T cells in mLNs. Values are presented as means ± SEMs (n = 4-7 mice per group from at least 2 independent experiments). C, IL-17/IL-13 expression in mLNs (gated on CD4+ T cells) at different time points. Dot plots (Fig 3, A and C) show 1 representative experiment of 3 independent experiments (at least 3 mice per group). ∗∗∗P < .001, ∗∗P < .01. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 In vitro conversion of TH17- but not TH2-polarized T cells into TH17/TH2 cells. A, Transgenic CD4+ T cells were polarized in vitro into TH2 (upper panel) or TH17 (lower panel) cells. TH cells were restimulated with OVA-DCs (left panel) or OVA-APCs (right panel) and examined for IL-13 and IL-17 expression. B, IL-4 expression in IL-17−IL-13− (filled histogram), IL-17+IL-13− (dashed line), IL-17−IL-13+ (dotted line), and IL-17+IL-13+ (full line) TH cells. Data are from 1 representative experiment of 2 independent experiments. C and D, OVA-DCs were cocultured with TH17 cells in different conditions. Values are presented as means ± SEMs of 4 independent experiments. CD30L, CD30 ligand; CD40L, CD40 ligand; CTLA4, cytotoxic T lymphocyte–associated antigen 4; Ham, hamster; NHIgG, normal human IgG; OX40L, OX40 ligand. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Identification of IL-17+IL-13+IL-4+CD4+ T cells (TH17/TH2) that coexpress GATA-3 and RORγt in inflamed lung tissues. Mice were injected with PBS-DCs or OVA-DCs intratracheally (IT; Fig 5, A) or intravenously (IV; Fig 5, A-C) at days 0 and 12 and killed on day 15. A, IL-13 and IL-17 expression among CD4+ T cells in lung tissues. B, IL-4 or GATA-3 expression according to IL-13/IL-17 profile. C, IL-4, IL-13, and IL-17 coexpression in CD4+GATA-3+ T cells. D, RORγt and GATA-3 coexpression in IL-17+IL-4+CD4+ T cells. Data are from 1 representative experiment of 2 independent experiments (3 mice per group). Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Airway host DCs convert effector CD4+ T cells into TH17/TH2 cells in vitro. CD45.2 mice were injected with OVA-CD45.1 DCs intratracheally or intravenously at days 0 and 12 and killed on day 15. OVA-DCs (CD45.1 DCs before injection) or FACS-sorted donor (CD45.1) and host (CD45.2) airway DCs were cocultured with TH2- or TH17-polarized cells (A) or lung effector CD4+ T cells (B). IL-13 and IL-17 expression in CD4+ T cells before (ex vivo) or after culture. Data are from 1 representative experiment of 4 or 3 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Repetitive local injection of OVA-DCs induces corticosteroid-resistant TH17 airway inflammation. Mice were injected with PBS-DCs or OVA-DCs intratracheally at days 0, 12, and 15. Some mice were treated daily with dexamethasone (DEX; 2.5 mg/kg administered intraperitoneally) at days 12 to 15. A, Differential cell count in bronchoalveolar lavage fluid. B, Lung sections stained with hematoxylin and eosin (H&E) and periodic acid–Schiff (PAS). C, Cytokine release by mLN cells after in vitro restimulation and lung explants. Values are presented as means ± SEMs of 6 mice per group. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 In vivo trafficking to lungs and mLNs of DCs injected intravenously. Carboxyfluorescein succinimidyl ester-labeled OVA-DCs were injected intravenously, and mice were killed 48 hours later. Inguinal lymph nodes (iLN), mLNs, and lung tissue were examined for the detection of carboxyfluorescein succinimidyl ester-labeled CD11c+ MHC class II+ DCs. Data represent 1 representative experiment of 2 experiments. IE, Anti-I-Ad/I-Ed. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Repetitive local or systemic administration of OVA-DCs induces neutrophil recruitment to airways. Mice were injected with PBS-DCs or OVA-DCs intratracheally (A) or intravenously (B) at days 0, 12, and 15. Differential proportion of infiltrating cells in bronchoalveolar lavage fluid is shown. Values are presented as means ± SEMs (n = 4-8 mice per group from 2 independent experiments). ∗∗∗P < .001, ∗∗P < .01, ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Inflammatory DCs and T-cell receptor stimulation are necessary to initiate TH17 responses. Mice were sensitized intravenously at days 0 and 12 with PBS-DCs, OVA-DCs, endotoxin-free OVA-DCs (OVA endo-DCs), or low-dose LPS-DCs. Mice were killed on day 15. A, Differential cell count in bronchoalveolar lavage fluid. B, Cytokine release in mLNs after OVA restimulation in vitro. Data are presented as means ± SEMs of 3 to 5 mice per group. C, IL-17/IL-13 expression in CD4+ T cells. Dot plots represent 1 representative of at least 3 mice per group. ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 TH17+TH2+ lung CD4+ T cells that express GATA-3 do not produce IFN-γ. Mice were injected with OVA-DCs intravenously at days 0 and 12 and killed on day 15. IL-13 and IL-17 expression among CD4+ T cells in lung tissues (left panel) and IFN-γ and GATA3 expression according to IL-17 and IL-13 expression (right panel). Data represent 1 representative experiment of 2 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 OVA-DCs convert lung effector CD4+ T cells into TH17+TH2+ cells that express GATA-3 in vitro. CD45.2 mice were injected with OVA-CD45.1 DCs intravenously at days 0 and 12 and killed on day 15. OVA-CD45.1 DCs were cocultured with lung effector CD4+ T cells. IL-13 and IL-17 expression among IL-4+CD4+ T cells that expressed GATA-3. Data are from 1 representative experiment of 2 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 192-201.e6DOI: (10.1016/j.jaci.2011.04.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions