T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death Hye Young Kim,

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T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death Hye Young Kim, PhD, Ya-Jen Chang, PhD, Ya-Ting Chuang, PhD, Hyun-Hee Lee, PhD, David I. Kasahara, PhD, Thomas Martin, MD, PhD, Joyce T. Hsu, MD, Paul B. Savage, PhD, Stephanie A. Shore, PhD, Gordon J. Freeman, PhD, Rosemarie H. DeKruyff, PhD, Dale T. Umetsu, MD, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 2, Pages 414-425.e6 (August 2013) DOI: 10.1016/j.jaci.2013.03.025 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TIM-1 is required for the development of ozone-induced AHR. A, Strategy for disruption of the TIM1 gene. Deletion of the TIM1 gene was confirmed by using PCR. RL, Lung resistance. B, Results represent changes in lung resistance in wild-type or TIM1−/− mice after air or ozone exposure. *P < .05 and **P < .01 compared with the air-exposed group (2-way ANOVA). C, Inflammatory cell numbers in BAL fluid of mice from Fig 1, B (cells per lung). *P < .05 and **P < .01 compared with the air-exposed group (2-tailed t test). D, Representative lung sections stained with hematoxylin and eosin (×10 magnification). E, Percentage of tetramer-positive T-cell receptor (TCR) β+ NKT cells in the lungs after exposure to either air or ozone (left) and total number of NKT cells (right). ***P < .001 (WT, air- vs ozone-exposed group) or ***P < .001 (WT vs TIM1−/− mice after ozone exposure; 2-tailed t test). Data are representative of at least 3 independent experiments with 3 to 5 mice per group. n.s, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TIM-1 is not required for the development of OVA-induced AHR. A, WT and TIM1−/− mice have AHR equivalently after sensitization and challenge with OVA. The graph represents the changes in lung resistance (RL). The TIM1−/− OVA group was compared with the WT OVA group (2-way ANOVA). B, Inflammatory cell numbers in BAL fluid after OVA challenge (cells per lung). The TIM1−/− OVA group was compared with the WT OVA group (2-tailed t test). Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils. C, The number of NKT cells was calculated as in Fig 1, G. Tetramer-positive T-cell receptor (TCR) β+ NKT cells after saline or OVA challenge (left) are shown, and graphs represent the total number of NKT cells in each group. ***P < .001 (WT) or ***P < .001 TIM1−/−, saline vs OVA group; not significant (WT vs TIM1−/− mice after OVA challenge; 2-tailed t test). Data are representative of at least 3 independent experiments with 3 to 5 mice per group. n.s, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Oxidative stress induces apoptosis in the airway. A, WT mice were exposed to air (top) or ozone (bottom) as in Fig 1, and lungs were taken 24 hours after the last ozone exposure for immunofluorescence staining: propidium iodide (PI; nuclear) staining is shown in red, and TUNEL staining is shown in green. Arrows indicate the apoptotic cells (yellow; original magnification ×40). Data are representative of 2 independent experiments with 3 to 4 mice in each group. B, WT or TIM1−/− mice were exposed to air (top) or ozone (bottom), and apoptotic epithelial cells (CD45− cells) were stained with Annexin V–fluorescein isothiocyanate (left panel). The graph represents the percentage of Annexin V+ cells in each group. TIM1−/− mice were compared with WT mice (not significant, 2-tailed t test). C, WT mice were exposed to air or ozone, and anti–TIM-1 (3D10) mAb was injected 24 hours before the first ozone exposure. Results represent the changes in lung resistance (RL). *P < .05 and **P < .01 compared with the air-exposed group (2-way ANOVA). D, Inflammatory cell numbers in BAL fluid of mice from Fig 1, A (cells per lung). *P < .05 and **P < .01 compared with air-exposed mice (2-tailed t test). Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils; n.s, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Apoptotic cells were critical for the development of ozone-induced AHR. A, Q-VD-OPH (2 mg/kg) was injected 24 hours before every ozone exposure, and AHR was measured 6 days after first exposure. *P < .05 compared with the air-exposed group (2-way ANOVA). B, Inflammatory cell numbers in BAL fluid (cells per lung). **P < .01 and ***P < .001 compared with the air-exposed group (2-tailed t test). Mac, Macrophage; Neu, neutrophils; n.s., not significant. C, Lung sections from the mice shown in Fig 4, A, stained with hematoxylin and eosin (original magnification ×10). D, Apoptotic airway epithelial cells (left) and the percentage of Annexin V+ cells in each group (right). Q-VD-OPH–treated mice were compared with ozone-exposed mice. *P < .05 (2-tailed t test). Data are representative of 2 independent experiments with 3 to 5 mice. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Apoptotic cells activate NKT cells through TIM-1. A, Apoptosis of a mouse airway epithelial cell line (MLE12) after hydrogen peroxide treatment was examined by using Annexin V and propidium iodide staining. B, WT or TIM1−/− NKT cells were cultured with a suboptimal dose of α-GalCer (1 ng/mL; [(−)]), an optimal dose of α-GalCer (100 ng/mL), live MLE12 cells plus suboptimal α-GalCer (1 ng/mL), apoptotic MLE12 cells plus suboptimal α-GalCer (1 ng/mL), or apoptotic MLE12 cells plus suboptimal α-GalCer (1 ng/mL) plus Annexin V (10 μg/mL) for 48 hours. Data are representative of at least 3 independent experiments. C, Human NKT cells were cultured with a suboptimal dose of α-GalCer (1 ng/mL [(−)]), an optimal dose of α-GalCer (100 ng/mL), live A549 cells plus suboptimal α-GalCer (1 ng/mL), apoptotic A549 cells plus suboptimal α-GalCer (1 ng/mL), or apoptotic A549 cells plus suboptimal α-GalCer (1 ng/mL) plus Annexin V (10 μg/mL) for 48 hours. NKT cells were then stained for intracellular cytokines. Data are representative of 3 independent experiments. D, The percentage of IL-4–producing NKT cells from all 3 experiments was calculated and graphed. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 TIM-1 expression by NKT cells is required for ozone-induced AHR. A, Schematic diagram of adoptive transfer of WT or TIM1−/− NKT cells. B, After repeated exposure to ozone, AHR was measured. **P < .01 compared with ozone-treated Jα18−/− mice (2-way ANOVA). C, Inflammatory cells in BAL fluid (cells per lung). Mac, Macrophage; Neu, neutrophils; n.s., not significant. *P < .05 and **P < .01 compared with ozone-treated Jα18−/− mice (2-tailed t test). D, WT or TIM1−/− mice were exposed to ozone as in Fig 1, A. Lung cells were prepared and stimulated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours. Cytokines produced from NKT cells were stained for intracellular IL-4, IL-13, and IL-17. *P < .05, TIM1−/− mice compared with ozone-treated WT mice (2-tailed t test). Data are representative of at least 2 independent experiments. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 RSV infection induces AHR in a TIM-1–dependent manner. A, WT or TIM1−/− mice were infected with RSV or sham infected, and lung resistance (RL) was measured on day 6 after infection. ***P < .001 compared with the sham-infected group (2-way ANOVA). B, BAL fluid was taken from the mice in Fig 7, A, and assessed for inflammatory cells (cells per lung). Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils. **P < .01, WT vs TIM1−/− mice infected with RSV (2-tailed t test). C, WT or CD1d−/− mice were infected with RSV or sham infected, and lung resistance (RL) was measured. ***P < .001, WT vs CD1d−/− mice infected with RSV (2-way ANOVA). D, BAL fluid was assessed for inflammatory cells. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils. **P < .01 and ***P < .001, WT RSV-infected group compared with CD1d−/− RSV-infected group (2-tailed t test). E, Tetramer-positive T-cell receptor (TCR) β+ NKT cells in BAL fluid after sham (left panels) or RSV (right panels) infection. FSC, Forward scatter; SSC, side scatter. F, The graph represents the percentage of Annexin V+ cells. ***P < .001 compared with the sham infected group (2-tailed t test). G, Q-VD-OPH (2 mg/kg) was injected before RSV infection, and AHR was measured. ***P < .001, compared with the RSV-infected group (2-way ANOVA). H, BAL fluid was taken from the mice in Fig 7, G, and assessed for inflammatory cells. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils. *P < .05 and **P < .01, RSV vs RSV plus Q-VD-OPH group (2-tailed t test). I, WT or TIM1−/− NKT cells (5 × 105 cells per mouse) were transferred into Jα18−/− recipients before RSV infection, and AHR was measured. **P < .01, Jα18 −/− mice with WT NKT cells compared with Jα18−/− mice with TIM1−/− NKT cells (2-way ANOVA). J, BAL fluid was assessed for inflammatory cells. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils. *P < .05, Jα18−/− mice transferred with WT NKT cells compared with Jα18−/− mice transferred with TIM1−/− NKT cells (2-tailed t test). Data are representative of at least 2 independent experiments with 4 to 6 mice in each group. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Schematic diagram of the role of TIM-1 in patients with nonallergic forms of asthma. In some forms of asthma (eg, associated with air pollution and RSV infection), apoptotic airway epithelial cells activate NKT cells through TIM-1 recognition of dead cells, and these in turn activate NKT cells, which induce airway inflammation and AHR. TCR, T-cell receptor. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 WT or TIM1−/− mice have similar numbers of immune cells. A, B and T cells (CD4/CD8). B, NKT cells from WT or TIM1−/− mice. FSC, Forward scatter; SSC, side scatter; TCR, T-cell receptor. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Plasmacytoid dendritic cells (pDCs) and activated B cells from TIM1−/− mice do not express TIM-1, as demonstrated by using flow cytometry. However, TIM-2 is expressed normally on TIM1−/− pDCs and B cells, confirming the specific absence of TIM-1 expression in TIM1−/− mice. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Q-VD-OPH (2 mg/kg) injected 24 hours before OVA challenge does not affect OVA-induced AHR. A, The graph represents changes in lung resistance (RL). B, Inflammatory cells in BAL fluid. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophage; Neu, neutrophils. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 WT or TIM1−/− NKT cells were incubated with apoptotic MLE12 or live MLE12 cells (as in Fig 5, B). Culture supernatants were analyzed for IL-4, IL-13, and IFN-γ production by using ELISA. AEC, Airway epithelial cells. Journal of Allergy and Clinical Immunology 2013 132, 414-425.e6DOI: (10.1016/j.jaci.2013.03.025) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions