Restoration of T-box–containing protein expressed in T cells protects against allergen- induced asthma Jung Won Park, MD, Hyun Jung Min, MS, Jung Ho Sohn,

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Restoration of T-box–containing protein expressed in T cells protects against allergen- induced asthma Jung Won Park, MD, Hyun Jung Min, MS, Jung Ho Sohn, BS, Joo Young Kim, PhD, Jeong Ho Hong, PhD, Kirsten S. Sigrist, BS, Laurie H. Glimcher, MD, PhD, Eun Sook Hwang, PhD Journal of Allergy and Clinical Immunology Volume 123, Issue 2, Pages 479-485.e6 (February 2009) DOI: 10.1016/j.jaci.2008.10.035 Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 DTg/KO mice express T-bet in a T cell–specific and doxycycline (Dox)–inducible manner. A, DTg/KO mice on the C57BL6 genetic background were given control (−) or doxycycline (+) water for 4 weeks (n = 6). T-bet expression was analyzed in the lymph nodes (LN), spleen (Sp), liver (Liv), and thymus (Thy) of DTg/KO mice. B-D, CD4+ and CD8+ T cells were isolated from C57BL6 WT and DTg/KO mice (n = 6) and stimulated with anti–T-cell receptor for 24 hours in the absence (−) or presence (+) of doxycycline. Whole cell extracts were resolved by means of SDS-PAGE and incubated with monoclonal T-bet antibody (Fig 1, B). Cell supernatants from the activated CD4+ and CD8+ T cells were collected for measuring the cytokines IFN-γ (Fig 1, C) and IL-2 (Fig 1, D). Data were expressed as means ± SD (n = 6). ∗∗P < .001. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 T-bet overexpression attenuates allergic airway inflammation. DTg/KO mice were sensitized and challenged with OVA concomitant with doxycycline (Dox) administration (n = 6 per group). A, AHR was measured by using airway resistance (RL) to methacholine. B, Immune cells in BALF were counted. C, IL-13 expression in BALF was measured by means of ELISA. D, Lung tissues were stained with PAS, and the number of PAS+ cells per millimeter of epithelial basement membrane was counted. Data are presented as means ± SD for 6 mice in each group. ns, Not significant; Mac, macrophages; Lym, lymphocytes; Eos, eosinophils; Neu, neutrophils. #P < .05, ∗P < .01. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 OVA-specific sIgE, IgG2a, and cytokines were modulated by T-bet. DTg/KO mice were sensitized and challenged with OVA concomitant with doxycycline (Dox) administration (n = 6 per group). OVA-specific sIgE (A) and IgG2a (B) levels were measured in the serum by means of ELISA. C, Lymphocytes were isolated from draining lymph nodes and stimulated with anti-CD3 (2 μg/mL) overnight. Supernatants were collected for measuring the cytokines IL-5 (Fig 3, C) and IFN-γ (D). Data are presented as means ± SD for 6 mice. #P < .05, ∗P < .01. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Chronic airway inflammation was attenuated by the induction of T-bet. A, Scheme of the chronic asthma murine model. B, Expression levels of T-bet were analyzed by means of immunoblotting with thymic extracts of 3 mice per group. C, AHR was measured based on airway resistance (RL) to methacholine (MCh) in 3 groups of doxycycline-fed mice (n = 6 per group). #P < .05. D, Cytospin preparations of immune cells in the BALF were counted. Dox, Doxycycline; KO, knockout; ns, not significant; Mac, macrophages; Lym, lymphocytes; Eos, eosinophils; Neu, neutrophils. #P < .05, ∗P < .01. Data are presented as means ± SD for 6 mice. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Restoration of T-bet expression modulates cytokine production. Lung homogenates were harvested from the Dox (knockout [KO]), Dox (DTg/KO), and DoxL (DTg/KO) groups (n = 6 per group), as depicted in Fig 4, A, and used for measuring the cytokines IFN-γ (A), IL-5 (B), and IL-13 (C). Lymphocytes were isolated from draining lymph nodes and stimulated with anti-CD3 antibody overnight, and supernatants were harvested for ELISA of IFN-γ (D), IL-5 (E), IL-13 (F), and IL-17 (G). Dox, Doxycycline; ns, Not significant; KO, knockout. #P < .05, ∗P < .01, ∗∗P < .001. Data are presented as means ± SD for 6 mice. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Goblet cell hyperplasia and collagen deposition were decreased by the induction of T-bet (n = 6 per group). Lung tissues were collected from the Dox (knockout [KO]), Dox (DTg/KO), and DoxL (DTg/KO) groups, as depicted in Fig 5, A, and cut at 5-μm thickness. A, Lung tissue sections were stained with PAS and Masson trichrome. B, Quantitative analysis of PAS+ cells was performed (n = 5). C, Collagen contents in the lung (n = 6) were calculated by using image analysis. ∗P < .01, ∗∗P < .001. Dox, Doxycycline; KO, knockout; ns, not significant. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Generation of DTg/KO mice Generation of DTg/KO mice. A, The TRE-T-bet and CD2-rtTA transgenes and the mutant T-bet allele of DTg/KO mice were genotyped by means of PCR as indicated. Asterisks indicate DTg/KO mice. B, WT, T-bet knockout, and DTg/KO mice were given control (−) or doxycycline water (+) for 14 days (n = 5), and thymic whole-cell extracts were analyzed for T-bet protein expression by means of immunoblotting with the 4B10 T-bet mAb and anti-β-actin antibody. C, B220+ cells were isolated from WT and DTg/KO mice (n = 4) and stimulated with phorbol 12-myristate 13-acetate and ionomycin for 24 hours in the absence (−) and presence (+) of doxycycline. Cell extracts were harvested and resolved by means of SDS-PAGE, followed by immunoblotting of T-bet. D, Cell supernatants were assayed for measuring IL-2 cytokines by means of ELISA. Data are presented as means ± SDs for 4 mice. Dox, Doxycycline; KO, knockout. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

T-bet deficiency increased allergen-induced airway inflammation T-bet deficiency increased allergen-induced airway inflammation. A, Scheme of the OVA-induced asthma murine model. WT and T-bet knockout (KO) mice were sensitized and challenged with 1% OVA or PBS (n = 5). Mice were analyzed at day 32. B, Lung tissues were sectioned and stained with PAS. C, IL-13 production was measured in lung homogenates by means of ELISA. Data are presented as means ± SD (n = 5). Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Asthma-related cytokines were increased in T-bet knockout (KO) mice Asthma-related cytokines were increased in T-bet knockout (KO) mice. WT and T-bet knockout mice were sensitized and challenged with OVA, as described in Fig E2 (n = 5). Single cell suspensions of lymphocytes were obtained from draining lymph nodes and stimulated with anti-CD3 overnight. Cell supernatants were collected for measuring the cytokines IL-2 (A), IL-5 (B), IL-13 (C), and IL-17 (D) by means of ELISA. Data are presented as means ± SD for 5 mice. ns, Not statistically significant. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Allergen-induced eosinophilic inflammation was protected by T-bet expression. A, Scheme of the allergen-induced asthma model. DTg/KO mice were sensitized and challenged with OVA and killed at day 32. B, Representative photomicrographs of PAS staining of lung sections are shown (n = 6 per group). ip, Intraperitoneal; Dox, doxycycline. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Progression of airway inflammation was attenuated by T-bet expression Progression of airway inflammation was attenuated by T-bet expression. A, Scheme of the allergen-induced asthma model. OVA-sensitized DTg/KO mice were fed with doxycycline water and challenged with OVA by means of intranasal administration (n = 6 per group). ip, Intraperitoneal; in, intranasal. B, AHR to methacholine (MCh) was measured in each group (n = 6). C, Immune cells in the BALF were counted (n = 6). Mac, macrophage; Lym, lymphocytes; Eos, eosinophils; Neu, neutrophils. D, Lung tissue sections were stained with PAS, and PAS+ cells counted are shown (n = 6). Data are presented as means ± SDs for 6 mice. ns, Not significant. #P < .05. Journal of Allergy and Clinical Immunology 2009 123, 479-485.e6DOI: (10.1016/j.jaci.2008.10.035) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions