T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production Ayako Matsuki, MD, Hiroaki Takatori, MD,

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T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production Ayako Matsuki, MD, Hiroaki Takatori, MD, PhD, Sohei Makita, MD, Masaya Yokota, MD, PhD, Tomohiro Tamachi, MD, PhD, Akira Suto, MD, PhD, Kotaro Suzuki, MD, PhD, Koichi Hirose, MD, PhD, Hiroshi Nakajima, MD, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 4, Pages 1355-1367.e6 (April 2017) DOI: 10.1016/j.jaci.2016.08.022 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IFN-γ induces T-bet expression in lung ILC2s. A, Thy1.2+ Lin− cells were isolated from the lung of WT mice and cultured with IL-2 and IL-7 in the presence or absence of IFN-γ for 6 days. mRNA levels of T-bet, IL-12Rβ2, and IFN-γ were analyzed by quantitative PCR. Naive CD4+ T cells, TH0 cells, and TH1 cells were used as controls. Data are means ± SD of 3 independent experiments. **P < .01. B, The expression of T-bet and GATA3 in lung CD25+ ST2+ Thy1.2+ Lin− cells or CD25− ST2− Thy1.2+ Lin− cells was examined by intracellular staining in WT mice. T-bet−/− mice were used as controls. Data are representative of 3 independent experiments. C, ST2+ Thy1.2+ Lin− cells were isolated from the lung of WT mice and cultured with IL-2 and IL-7 in the presence or absence of IFN-γ and/or IL-33 for 6 days. Representative data of T-bet staining and means ± SD of the frequency of T-bet–expressing cells are shown. Data are representative of 3 independent experiments. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-33–induced eosinophilic airway inflammation is exacerbated in T-bet−/− mice. A, Representative CD11c vs Siglec-F staining, and means ± SD of the frequency and absolute numbers of Siglec-F+ CD11c− cells (eosinophils) in the BALF are shown (n = 5, each). *P < .05. B, Representative photomicrographs (H&E staining) and means ± SD of histological score of the lung are shown. n = 4, each. Scale bars, 100 μm. *P < .05. C, Representative photomicrographs (periodic acid-Schiff staining) and means ± SD of goblet cell score are shown. n = 4, each. Scale bars, 50 μm. *P < .05. D, Means ± SD of the levels of IL-4, IL-5, and IL-13 in the BALF are shown (n = 3, each). ND, Not detectable; NS, not significant. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IL-33–induced accumulation of lung ILC2s is exacerbated in T-bet−/− mice. A, Representative Lin vs Thy1.2 staining of isolated lung cells, and means ± SD of the frequency and absolute numbers of Thy1.2+ Lin− cells in the lung are shown (n = 5, each). *P < .05. B, Means ± SD of the frequency of CD25+ cells in Thy1.2+ Lin− cells and absolute numbers of CD25+ Thy1.2+ Lin− cells in the lung are shown (n = 3, each). NS, Not significant. *P < .05. C, Means ± SD of the frequency of ST2+ cells and KLRG1+ cells in CD25+ Thy1.2+ Lin− cells and absolute numbers of ST2+ CD25+ Thy1.2+ Lin− cells and KLRG1+ CD25+ Thy1.2+ Lin− cells are shown (n = 3, each). D, Isolated lung cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours, and subjected to intracellular staining for IL-4, IL-5, IL-13, and IL-17A. Shown are representative Thy1.2 vs IL-4, IL-5, IL-13, or IL-17A staining of Thy1.2+ Lin− cells and means ± SD of the frequency of the indicated cells (n = 3, each). Data are representative of 4 independent experiments. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 T-bet expressed in non-T/non-B cells is involved in the suppression of IL-33–induced eosinophilic airway inflammation. A, Representative CD11c vs Siglec-F staining of BALF cells and means ± SD of the absolute numbers of Siglec-F+ CD11c− cells in the BALF are shown (n = 3, each). B, Representative Lin vs Thy1.2 staining of isolated lung cells and means ± SD of the absolute numbers of Thy1.2+ Lin− in the lung are shown (n = 3, each). *P < .05. C, Representative histogram of CD25 staining gating on Thy1.2+ Lin− cells and means ± SD of the frequency of CD25+ cells are shown (n = 3, each). *P < .05. D, Representative histogram of ST2 or KLRG1 staining gating on CD25+ Thy1.2+ Lin− cells and means ± SD of the frequency of ST2+ or KLRG1+ cells are shown (n = 3, each). **P < .01. E, Isolated lung cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours, and subjected to intracellular staining for IL-4, IL-5, IL-13, and IL-17A. Shown are representative CD25 vs IL-4, IL-5, IL-13, or IL-17A staining of Thy1.2+ Lin− cells and means ± SD of the frequency of cytokine-producing cells (n = 3, each). NS, Not significant. Data are representative of 3 independent experiments. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 T-bet suppresses IL-9 production in lung ILC2s. A, Isolated lung Thy1.2+ Lin− cells from WT mice and T-bet−/− mice were cultured with IL-2 and IL-7 in the presence or absence of IL-33 for 6 days, and RNA-Seq analysis was performed. Shown is a heatmap of top 10 genes whose expression is upregulated in IL-33–stimulated T-bet−/− Thy1.2+ Lin− cells. B, Isolated lung Thy1.2+ Lin− cells from IL-33–stimulated WT mice and T-bet−/− mice were cultured with IL-2, IL-7, and IL-33 for 6 days, and mRNA levels for indicated cytokines were analyzed by quantitative PCR. Data are means ± SD of 3 independent experiments. *P < .05. C, Isolated lung Thy1.2+ Lin− cells from IL-33–stimulated WT mice and T-bet−/− mice were cultured with IL-2, IL-7, and IL-33 for 6 days and then subjected to flow-cytometric analysis. Representative CD25 vs ST2 staining (upper panels) and IL-5 vs IL-9 staining gating on CD25+ population (lower panels) are shown. Data are representative of 3 independent experiments. D, Isolated lung ST2+ Thy1.2+ Lin− cells from WT mice and T-bet−/− mice were cultured with IL-2 and IL-7 in the presence or absence of anti–IL-9 antibody for 6 days, and the number of surviving cells was analyzed. Data are means ± SD of surviving cells. *P < .05, **P < .01. E, Isolated lung Thy1.2+ Lin− cells from IL-33–stimulated WT mice were stimulated with IL-2, IL-7, and IL-33 for 24 hours. These cells were infected with retroviruses of MIG (as a control) or MIG-T-bet, cultured for 4 days in the presence of IL-2, IL-7, and IL-33, and subjected to flow-cytometric analyses. Shown are representative fluorescence-activated cell sorting profiles of ST2 vs KLRG1, IL-5 vs IL-13, and IL-5 vs IL-9 gating on GFP+ CD25+ cells. Data are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Anti–IFN-γ antibody enhances IL-33–induced IL-9 production from ILC2s in WT mice but not in T-bet−/− mice. Representative CD25 vs IL-9 staining (A) and CD25 vs T-bet staining (B) of Thy1.2+ Lin− cells in the lung and means ± SD of the absolute numbers of IL-9–producing CD25+ Thy1.2+ Lin− cells in the lung are shown (n = 3, each). Results are representative of 2 independent experiments. NS, Not significant. *P < .05. **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Anti–IL-9 antibody cancels the enhanced IL-33–induced airway inflammation in T-bet−/− mice. A, Representative CD11c vs Siglec-F staining of BALF cells and means ± SD of the absolute numbers of Siglec-F+ CD11c− cells in the BALF are shown (n = 3, each). *P < .05. B, Representative Lin vs Thy1.2 staining of isolated lung cells and means ± SD of the absolute numbers of Thy1.2+ Lin− cells and CD25+ Thy1.2+ Lin− cells in the lung are shown (n = 3, each). Results are representative of 2 independent experiments. NS, Not significant. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 T-bet is dispensable for the development of ILCs in the lung. A-D, Single-cell suspensions of lung cells were isolated from WT mice and T-bet−/− mice at steady-state conditions and subjected to flow-cytometric analysis. A, Representative lineage markers (Lin) vs Thy1.2 staining of isolated lung cells, and means ± SD of the frequency and absolute numbers of Thy1.2+ Lin− cells in the lung are shown (n = 3, each). B, Representative histograms of CD25 staining gating on Thy1.2+ Lin− cells, and means ± SD of the frequency of CD25+ cells and absolute numbers of CD25+ Thy1.2+ Lin− cells are shown (n = 3, each). C, Isolated lung cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours, and subjected to intracellular staining for IL-4, IL-5, IL-13, and IL-17A. Representative Thy1.2 vs IL-4, IL-5, IL-13, or IL-17A staining of Thy1.2+ Lin− cells, and means ± SD of the frequencies of cytokine-producing cells are shown (n = 3, each). D, Means ± SD of mean fluorescent intensity (MFI) for GATA3 and RORγt staining of lung Thy1.2+ Lin− cells are shown (n = 3, each). NS, Not significant. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Eosinophilic inflammation is exacerbated in T-bet−/− mice upon IL-25 or papain administration. IL-25 (1 μg) or papain (25 μg) was administered to WT mice and T-bet−/− mice intranasally at days 0, 3, and 6. Twelve hours after the last administration, cells harvested from the BALF were subjected to flow-cytometric analysis. Representative CD11c vs Siglec-F staining of BALF cells and means ± SD of the absolute numbers of Siglec-F+ CD11c− cells in the BALF are shown (n = 3, each). Data are representative of 2 independent experiments. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 The frequency and cytokine production of CD4+ T cells in IL-33–stimulated T-bet−/− mice. A and B, IL-33 was administered to WT mice and T-bet−/− mice intranasally as described in the Methods section. A, Twelve hours after the last administration, isolated lung cells were subjected to flow-cytometric analysis. Representative CD3ε vs CD19 staining of single-cell suspensions of lung cells and CD4 vs CD8 staining of CD3ε+ cells are shown. B, Isolated lung cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours and subjected to intracellular staining for IL-4, IL-5, and IL-13. Shown are representative IL-5 vs IL-4 and IL-5 vs IL-13 staining of CD4+ cells. Data are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 The expression levels of TH9 cell–related genes in Thy1.2+ Lin− cells. Isolated lung Thy1.2+ Lin− cells from IL-33–stimulated WT mice and T-bet−/− mice were cultured with IL-2, IL-7, and IL-33 for 6 days, and mRNA levels for indicated molecules were analyzed by quantitative PCR. Data are means ± SD of 3 independent experiments. ND, Not detectable. Journal of Allergy and Clinical Immunology 2017 139, 1355-1367.e6DOI: (10.1016/j.jaci.2016.08.022) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions