Interferon response factor 3 is essential for house dust mite–induced airway allergy Thomas Marichal, DVM, Denis Bedoret, DVM, PhD, Claire Mesnil, DVM,

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Interferon response factor 3 is essential for house dust mite–induced airway allergy Thomas Marichal, DVM, Denis Bedoret, DVM, PhD, Claire Mesnil, DVM, Muriel Pichavant, PhD, Stanislas Goriely, PhD, François Trottein, PhD, Didier Cataldo, MD, PhD, Michel Goldman, MD, PhD, Pierre Lekeux, DVM, PhD, Fabrice Bureau, DVM, PhD, Christophe J. Desmet, PhD Journal of Allergy and Clinical Immunology Volume 126, Issue 4, Pages 836-844.e13 (October 2010) DOI: 10.1016/j.jaci.2010.06.009 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IRF3−/− mice are protected from HDM-induced airway allergy. WT and IRF3−/− mice were treated once a week for 3 consecutive weeks with saline or HDM. A, Total and differential immune cell counts in bronchoalveolar lavage fluid (BALF). B and C, Hematoxylin and eosin (Fig 1, B) and periodic acid–Schiff (Fig 1, C) staining of lung sections (original magnification ×100). D, ELISA measurement of serum IgE levels. E, Measurement of dynamic airway resistance (n = 6). Comparable results were obtained in 3 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IRF3−/− mice display impaired TH2 cytokine secretion and HDM-specific TH2 cell differentiation in response to HDM. A, Proliferation of BLN cells from saline- or HDM-treated WT and IRF3−/− mice after in vitro HDM stimulation. B, ELISA measurement of IL-4, IL-5, IL-13, and IFN-γ in the supernatants of HDM-stimulated BLN cells. C, Percentages among CD4+ BLN cells of activated CD4+ T cells that proliferated in response to HDM (identified as CD4+ CFSElow cells). D, Representative histograms of samples compared in Fig 2, C. E, Percentages of IL-4+ cells among CD4+ CFSElow cells (n = 4). Comparable results were obtained in 3 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Immature phenotype and deficient migration of lung DCs from IRF3−/− mice on HDM exposure. A, Expression of MHC class II, CD40, and CD86 on lung DCs of saline- or HDM-treated WT and IRF3−/− mice. B, Number of DCs in the BLNs of saline- and HDM-treated WT and IRF3−/− mice. C, Number of CFSE+ DCs in the BLNs of WT mice transferred with PBS- or HDM-treated lung DCs labeled with CFSE (n = 4). Comparable results were obtained in 3 independent experiments. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Deficient maturation of IRF3−/− BMDCs exposed to HDM in vitro. A, Expression of MHC class II, CD40, and CD86 on saline- or HDM-treated WT and IRF3−/− BMDCs. B, ELISA measurement of IL12p70 secretion in the supernatants of BMDC cultures (n = 3). Comparable results were obtained in 3 independent experiments. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 HDM-loaded IRF3−/− DCs do not induce airway allergy. WT mice received intratracheal saline (Ctrl-BMDCs)– or HDM (HDM-BMDCs)–loaded WT or IRF3−/− BMDCs and were challenged with intranasal HDM. A, Total and differential immune cell counts in the bronchoalveolar lavage fluid (BALF). B and C, Hematoxylin and eosin (Fig 5, B) and periodic acid–Schiff (Fig 5, C) staining of lung sections (original magnification ×100). D, BLN cell proliferation in response to in vitro HDM stimulation. E, ELISA for IL-4, IL-5, IL-13, and IFN-γ on culture supernatants of HDM-stimulated BLN cells (n = 6). Comparable results were obtained in 3 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Type I interferon–independent maturation of DCs in response to HDM. A, ELISA measurement of IFN-β1 secretion in the supernatants of saline- or HDM-treated WT and IRF3−/− BMDCs. B, Expression of MHC class II, CD40, and CD86 on WT and IRF3−/− BMDCs treated with saline, HDM, or HDM and 250 pg/mL recombinant IFN-β1 (n = 3). Comparable results were obtained in 3 independent experiments. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IRF 3−/− mice are protected from HDM-induced allergic airway inflammation and mucus cell hyperplasia. A, Inflammatory scores estimated from hematoxylin and eosin staining of lung sections. B, Percentage of periodic acid–Schiff (PAS)–stained goblet cells per total epithelial cells (n = 6). Comparable results were obtained in 3 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IRF 7−/− mice are not protected from HDM-induced airway allergy IRF 7−/− mice are not protected from HDM-induced airway allergy. WT and IRF7−/− mice were treated once a week for 3 consecutive weeks with saline or HDM. A, Total and differential immune cell counts in bronchoalveolar lavage fluid (BALF). B and C, Representative section (original magnification ×100; Fig E2, B) and inflammatory scores (Fig E2, C) of hematoxylin and eosin–stained lung sections. D and E, Representative staining (original magnification ×100; Fig E2, D) and percentage (Fig E2, E) of periodic acid–Schiff–stained goblet cells per total epithelial cells in randomly selected bronchi. F, ELISA measurement of serum IgE levels. G, Measurement of dynamic airway resistance (n = 6). Comparable results were obtained in 3 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

WT and IRF3−/− T lymphocytes have similar proliferation potential WT and IRF3−/− T lymphocytes have similar proliferation potential. Proliferation of T cells purified from BLNs of WT and IRF3−/− mice (>95% purity) after stimulation with anti-CD28 and anti-CD3 antibodies is shown. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Representative histograms of the expression of MHC class II, CD40, and CD86 on lung DCs of saline- or HDM-treated WT and IRF3−/− mice 18 hours after treatment. Inserts indicate the mean fluorescence intensity of the signal for each marker in saline-treated (gray font) and HDM-treated (black font) mice. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Representative histograms of the expression of MHC class II, CD40, and CD86 on saline- or HDM-treated WT and IRF3−/− BMDCs after overnight treatment. Inserts indicate the mean fluorescence intensity of the signal for each marker in saline-treated (gray font) and HDM-treated (black font) BMDCs. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HDM -loaded IRF3−/− DCs do not induce allergic airway inflammation and mucus cell hyperplasia. WT mice received intratracheal saline (Ctrl-BMDCs)– or HDM (HDM-BMDCs)–loaded WT or IRF3−/− BMDCs and were challenged with intranasal HDM. A, Inflammatory scores estimated from hematoxylin and eosin staining of lung sections. B, Percentage of periodic acid Schiff (PAS)–stained goblet cells per total epithelial cells (n = 6). Comparable results were obtained in 3 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IRF 3−/− mice display normal airway allergy after transfer of WT HDM-loaded DCs. WT and IRF3−/− mice received intratracheal saline (Ctrl-BMDCs)– or HDM (HDM-BMDCs)–loaded WT BMDCs and were challenged with control or HDM-WT BMDCs and a low dose of HDM. A, Total and differential immune cell counts in the bronchoalveolar lavage fluid (BALF). B and C, Representative section (original magnification ×100; Fig E7, B) and inflammatory scores (Fig E7, C) of hematoxylin and eosin staining of lung sections. D and E, Representative staining (original magnification ×100; Fig E7, D) and percentage (Fig E7, E) of periodic acid Schiff–stained goblet cells per total epithelial cells in randomly selected bronchi. F, BLN cell proliferation in response to in vitro HDM stimulation. G, ELISA for IL-4, IL-5, IL-13, and IFN-γ on culture supernatants of HDM-stimulated BLN cells (n = 4). Comparable results were obtained in 2 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IRF3−/− DCs induce normal TH2 responses when stimulated with an IRF3-independent adjuvant. WT and IRF3−/− BMDCs were loaded (OVA-BMDCs) or not (Ctrl-BMDCS) with OVA and stimulated with Pam3CSK4 before intratracheal administration to WT recipient mice. A, BLN cell proliferation in response to in vitro OVA stimulation. B, ELISA for IL-4, IL-5, IL-13, and IFN-γ on culture supernatants of OVA-stimulated BLN cells (n = 4). Comparable results were obtained in 2 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Representative histograms of the expression of MHC class II, CD40, and CD86 on WT and IRF3−/− BMDCs treated with saline, HDM, or HDM and 250 pg/mL recombinant IFN-β1 18 hours after treatment. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HDM -induced TH2 responses and airway allergy are independent of type I interferon signaling. WT and IFNAR2−/− mice were treated once a week for 3 consecutive weeks with saline or HDM. A, Total and differential immune cell counts in the bronchoalveolar lavage fluid (BALF). B and C, Representative section (original magnification ×100; Fig E10, B) and inflammatory scores (Fig E10, C) of hematoxylin and eosin staining of lung sections. D and E, Representative staining (original magnification ×100; Fig E10, D) and percentage (Fig E10, E) of periodic acid–Schiff–stained goblet cells per total epithelial cells in randomly selected bronchi. F, ELISA measurement of serum IgE levels. G, Number of DCs in the BLNs of saline- and HDM-treated WT and IFNAR2−/− mice. H, BLN cell proliferation in response to in vitro HDM stimulation. I, ELISA for IL-4, IL-5, IL-13, and IFN-γ on culture supernatants of HDM-stimulated BLN cells (n = 4). Comparable results were obtained in 2 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IRF3-dependent TH2 responses and airway allergy in response to HDM are independent of TRIF signaling. WT and TRIF−/− mice were treated once a week for 3 consecutive weeks with saline or HDM. A, Total and differential immune cell counts in the bronchoalveolar lavage fluid (BALF). B and C, Representative section (original magnification ×100; Fig E11, B) and inflammatory scores (Fig E11, C) of hematoxylin and eosin staining of lung sections. D and E, Representative staining (original magnification ×100; Fig E11, D) and percentage (Fig E11, E) of periodic acid–Schiff–stained goblet cells per total epithelial cells in randomly selected bronchi. F, ELISA measurement of serum IgE levels. G, Number of DCs in the BLNs of saline- and HDM-treated WT and TRIF−/− mice. H, BLN cell proliferation in response to in vitro HDM stimulation. I, ELISA for IL-4, IL-5, IL-13, and IFN-γ on culture supernatants of HDM-stimulated BLN cells (n = 4). Comparable results were obtained in 2 independent experiments. Journal of Allergy and Clinical Immunology 2010 126, 836-844.e13DOI: (10.1016/j.jaci.2010.06.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions