Innate immune responses during respiratory tract infection with a bacterial pathogen induce allergic airway sensitization Nicolas W.J. Schröder, MD,

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Innate immune responses during respiratory tract infection with a bacterial pathogen induce allergic airway sensitization Nicolas W.J. Schröder, MD, Timothy R. Crother, PhD, Yoshikazu Naiki, PhD, Shuang Chen, MD, Michelle H. Wong, MD, Atilla Yilmaz, MD, Anatoly Slepenkin, PhD, Danica Schulte, MD, Randa Alsabeh, MD, Terence M. Doherty, BA, Ellena Peterson, MD, Andre E. Nel, MD, Moshe Arditi, MD Journal of Allergy and Clinical Immunology Volume 122, Issue 3, Pages 595-602.e5 (September 2008) DOI: 10.1016/j.jaci.2008.06.038 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Low-dose live C pneumoniae infection induces allergic airway sensitization to HSA. A, Groups of mice were infected as indicated. Starting with day 0, mice received either 3 consecutive intranasal injections of HSA (n = 13 for low dose and n = 9 for high dose) or PBS control (n = 13 for low dose and n = 8 for high dose). Some mice were infected with 0.5 × 106C pneumoniae, and sensitization with HSA (day 0) was started 10 days after infection (n = 9) or PBS control (n = 10). Mice were challenged with HSA starting on day 15. One control group received PBS during the challenge period (n = 10). B, Eosinophil (eos) numbers per lung section, with representative lung sections (100-fold magnification) are shown at the right of the graph. C, Goblet cell numbers related to bronchial basal membrane length. Representative periodic acid–Schiff–stained sections (200-fold magnification) are shown. D, HSA-specific IgE, IgG1, and IgG2a titers of mice sensitized and challenged with HSA after infection. ∗P ≤ .05, ∗∗P ≤ .01. ns, Not significant compared with control animals. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Characteristics of pulmonary DCs in C pneumoniae–infected mice. A, Paraffin-embedded sections were stained with MIDC-8 to detect DCs. Total numbers of MIDC-8+ cells in 4 separate sections were counted (6 mice per group). B, Upregulation of costimulatory molecules assessed by means of staining of lung leukocytes with antibodies against CD11c, CD11b, and MHC class II. Shown are uninfected control animals (gray), mice infected with high-dose C pneumoniae (dotted line) or low-dose C pneumoniae (bold line) 5 days before analysis, and mice infected with low-dose C pneumoniae 10 days before analysis (thin line). These are representative results from 1 of 3 experiments performed with 5 mice. C, Numbers of FITC+ DCs in mediastinal lymph nodes (LN) after infection and intratracheal injection of 100 μg of FITC–HSA 24 hours before analysis. Cells were gated for CD11b. Shown are representative dot blots of cells (FITC–HSA × CD11c), as well as combined results of 3 separate experiments (n = 4 mice per experiment). ∗P ≤ .05. ND, Not determined. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 DCs from C pneumoniae–infected mice pulsed with HSA can adoptively transfer allergic airway sensitization. A, DCs were isolated from lungs of mice 5 or 10 days after infection with low-dose C pneumoniae or sham infection. DC expression of MHC class II expression by infected mice and control animals was determined by means of FACS. Cells were incubated with either PBS or HSA overnight and transferred to recipient mice by means of intratracheal inoculation (500,000 cells per mouse) on day 0. Mice were challenged with HSA starting on day 15. B, Eosinophil (eos) numbers in lung sections from mice that received control DCs pulsed with HSA (n = 5) or DCs from infected mice pulsed with either HSA (n = 7) or PBS (n = 8). C, Goblet cell numbers assessed by means of periodic acid–Schiff staining. Shown are combined results from 3 experiments. ∗P ≤ .05 D, Cytokine production by lymph node (LN) cells after in vitro restimulation with HSA. Shown are representative results from 1 of 3 experiments performed. E, IL-6 RNA content of pulmonary DCs of mice 5 days and 10 days after infection. IL-6 RNA was measured by using TaqMan real-time RT-PCR and compared with that seen in DCs of uninfected control mice. Combined data of 4 mice per group are shown. F, Percentage of lung CD4+CD25+Foxp3+ Treg cells in naive wild-type mice (n = 6-9 mice) 5 days after infection with either 5 × 105 or 5 × 106C pneumoniae or 10 days after infection with 0.5 × 106 administered intranasally. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Treg cells regulate airway sensitization induced by C pneumoniae (CP) infection. A, Infection, Treg cell depletion, and sensitization/challenge protocol: mice were infected with 0.5 × 106C pneumoniae on day −10, followed by a single intraperitoneal injection of 100 μg of PC61 antibody (n = 8) or rat IgG1 isotype control (n = 7) at day −2. Mice were then exposed to HSA on 3 consecutive days, followed by HSA challenge 2 weeks later. Control mice were injected with PC61 or isotype control (n = 8 and n = 7, respectively) without prior infection, followed by HSA injection on days 0 to 2. B and C, Eosinophil (eos) numbers and goblet cell numbers. D, HSA-specific IgE titers. ∗P ≤ .05. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 MyD88-dependent signaling in DCs is required for airway sensitization. A and B, Eosinophil (eos) numbers and goblet cell numbers in lung sections from wild-type mice (n = 7) infected with 0.5 × 106 live C pneumoniae, exposed to HSA on 3 consecutive days, and challenged with HSA, as shown in Fig 1, A. Data obtained from MyD88−/− mice (n = 8 mice are shown in comparison). ∗P ≤ .05, ∗∗P ≤ .01. ns, Not significant. Wild-type mice (n = 7) and MyD88−/− mice (n = 6) were infected with 0.5 × 106C pneumoniae and killed after 5 days. C, Upregulation of MHC class II, CD80, CD86, and CD40 in DCs of infected mice (bold line, wild-type mice; dotted line, MyD88−/− mice) versus uninfected control animals (gray, wild-type mice; dark gray, MyD88−/− mice) determined by means of FACS. DCs were identified as CD11c+/CD11b+. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Characteristics of pneumonia caused by low-dose and high-dose C pneumoniae at day 5 or low-dose C pneumoniae at day 10. Mice (n = 6 per group) were infected by means of intranasal injection of either 0.5 × 106 or 5 × 106 IFU of C pneumoniae 5 days or 0.5 × 106C pneumoniae 10 days before analysis. A, Representative hematoxylin and eosin–stained sections of paraffin-embedded lungs. B, Inflammatory scores obtained from hematoxylin and eosin–stained sections and levels of IL-6, TNF-α, IFN-γ, and IL-5 in the BAL fluid. ∗P ≤ .05, ∗∗P ≤ .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Cytokine production and expression of costimulatory molecules in DCs isolated from C pneumoniae–infected mice. Mice were infected with either 0.5 × 106 or 5 × 106 IFU of C pneumoniae, and lung leukocytes were prepared as described in the Methods section. A, Cells were stained for expression of CD11b and CD11c, and staining for intracellular cytokines was performed with antibodies against IL-10–phycoerythrin or IL-12–phycoerythrin. B, Upregulation of costimulatory molecules assessed by staining of lung leukocytes with antibodies against CD11c, CD11b, CD40, CD80, and CD86. Shown are uninfected control animals (gray), mice infected with high-dose C pneumoniae (dotted line) or low-dose C pneumoniae (bold line) 5 days before analysis, and mice infected with low-dose C pneumoniae 10 days before analysis (thin line). Shown are representative results from 1 of 3 experiments performed with 5 mice. C, Total numbers of MHC class IIhigh DCs in mediastinal lymph nodes (LN) 5 days after infection. Shown are representative dot blots of cells gated for CD11b, as well as combined results of 3 separate experiments (n = 4 per group). D, Percentages of DCs in infected mice undergoing apoptosis. DCs were identified by using CD11c, CD11b, and side-scatter. Apoptotic cells were identified with the Vybrant Apoptosis Assay Kit (Invitrogen). Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Depletion of CD4+CD25+ Treg cells in the lungs after injection of anti-CD25 antibody. Mice received intraperitoneal injections of 100 μg of either anti-CD25 antibody (clone PC61) or rat IgG1 isotype control on day 0. Mice were killed 2 or 4 days after injection. Splenocytes and lung leukocytes were prepared as described in the Methods section and were then analyzed for Foxp3+ Treg cells by means of flow cytometry with antibodies against CD4, CD25 (clone 7D4), and Foxp3. Percentages refer to total CD4+ lymphocytes. Shown are representative results from 1 of 3 experiments performed with 3 mice. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

MyD88-dependent signaling in DCs is required for airway sensitization MyD88-dependent signaling in DCs is required for airway sensitization. BMDCs from wild-type (wt) and MyD88−/− mice were exposed to C pneumoniae (multiplicity of infection = 2.5) and HSA (50 μg/mL) in the presence of gentamicin for 16 hours, followed by intratracheal transfer into recipient mice. Wild-type mice were injected with wild-type DCs (n = 8) or MyD88−/− DCs (n = 11). One group of MyD88−/− mice received wild-type DCs (n = 10). A, Inflammatory scores determined by using hematoxylin and eosin–stained lung sections. B and C, Eosinophil (eos) numbers and goblet cell numbers in lung sections. ∗P ≤ .05, ∗∗P ≤ .01, ∗∗∗P ≤ .001. D, BMDCs generated from wild-type and MyD88−/− mice were infected with C pneumoniae (multiplicity of infection = 2.5), and content of C pneumoniae was determined after 24 hours by means of immunofluorescence with the Pathfinder staining kit (Sigma). Shown are representative results from 1 of 3 separate experiments. Journal of Allergy and Clinical Immunology 2008 122, 595-602.e5DOI: (10.1016/j.jaci.2008.06.038) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions