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• W1834477603 abstract "Research Article3 May 2011Open Access IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease Ourania Koltsida Ourania Koltsida Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece Search for more papers by this author Michael Hausding Michael Hausding Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Medicine, University of Mainz, Germany Search for more papers by this author Athanasios Stavropoulos Athanasios Stavropoulos Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece Search for more papers by this author Sonja Koch Sonja Koch Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany Search for more papers by this author George Tzelepis George Tzelepis Department of Pathophysiology, University of Athens Medical School, Athens, Greece Search for more papers by this author Caroline Übel Caroline Übel Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany Search for more papers by this author Sergei V. Kotenko Sergei V. Kotenko Department of Biochemistry and Molecular Biology, New Jersey Medical School, New Jersey, USA Search for more papers by this author Paschalis Sideras Paschalis Sideras Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece Search for more papers by this author Hans A. Lehr Hans A. Lehr Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland Search for more papers by this author Marcus Tepe Marcus Tepe Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Medicine, University of Mainz, Germany Search for more papers by this author Kevin M. Klucher Kevin M. Klucher Department of Hematology and Oncology, ZymoGenetics, Seattle, WA, USA Search for more papers by this author Sean E. Doyle Sean E. Doyle Department of Hematology and Oncology, ZymoGenetics, Seattle, WA, USA Search for more papers by this author Markus F. Neurath Markus F. Neurath I. Medical Clinic, University of Erlangen-Nürnberg, Germany Search for more papers by this author Susetta Finotto Corresponding Author Susetta Finotto [email protected] Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany These authors contributed equally to this manuscript Search for more papers by this author Evangelos Andreakos Corresponding Author Evangelos Andreakos [email protected] Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece These authors contributed equally to this manuscript Search for more papers by this author Ourania Koltsida Ourania Koltsida Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece Search for more papers by this author Michael Hausding Michael Hausding Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Medicine, University of Mainz, Germany Search for more papers by this author Athanasios Stavropoulos Athanasios Stavropoulos Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece Search for more papers by this author Sonja Koch Sonja Koch Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany Search for more papers by this author George Tzelepis George Tzelepis Department of Pathophysiology, University of Athens Medical School, Athens, Greece Search for more papers by this author Caroline Übel Caroline Übel Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany Search for more papers by this author Sergei V. Kotenko Sergei V. Kotenko Department of Biochemistry and Molecular Biology, New Jersey Medical School, New Jersey, USA Search for more papers by this author Paschalis Sideras Paschalis Sideras Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece Search for more papers by this author Hans A. Lehr Hans A. Lehr Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland Search for more papers by this author Marcus Tepe Marcus Tepe Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Medicine, University of Mainz, Germany Search for more papers by this author Kevin M. Klucher Kevin M. Klucher Department of Hematology and Oncology, ZymoGenetics, Seattle, WA, USA Search for more papers by this author Sean E. Doyle Sean E. Doyle Department of Hematology and Oncology, ZymoGenetics, Seattle, WA, USA Search for more papers by this author Markus F. Neurath Markus F. Neurath I. Medical Clinic, University of Erlangen-Nürnberg, Germany Search for more papers by this author Susetta Finotto Corresponding Author Susetta Finotto [email protected] Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany These authors contributed equally to this manuscript Search for more papers by this author Evangelos Andreakos Corresponding Author Evangelos Andreakos [email protected] Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece These authors contributed equally to this manuscript Search for more papers by this author Author Information Ourania Koltsida1, Michael Hausding2, Athanasios Stavropoulos1, Sonja Koch3, George Tzelepis4, Caroline Übel3, Sergei V. Kotenko5, Paschalis Sideras1, Hans A. Lehr6, Marcus Tepe2, Kevin M. Klucher7, Sean E. Doyle7, Markus F. Neurath8, Susetta Finotto *,3 and Evangelos Andreakos *,1 1Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece 2Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Medicine, University of Mainz, Germany 3Laboratory of Cellular and Molecular Immunology of the Lung, Institute of Molecular Pneumology, University of Erlangen-Nürnberg, Germany 4Department of Pathophysiology, University of Athens Medical School, Athens, Greece 5Department of Biochemistry and Molecular Biology, New Jersey Medical School, New Jersey, USA 6Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland 7Department of Hematology and Oncology, ZymoGenetics, Seattle, WA, USA 8I. Medical Clinic, University of Erlangen-Nürnberg, Germany *Susetta Finotto, Tel: +49 09131 8535883; Fax: +49 09131 8535977Evangelos Andreakos, Tel: +30 210 6597338; Fax: +30 210 6597545 EMBO Mol Med (2011)3:348-361https://doi.org/10.1002/emmm.201100142 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract IL-28 (IFN-λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-γ. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28Rα−/− mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c+ dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-γ−/− mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c+ cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c+ DC function in experimental allergic asthma. →See accompanying Closeup by Michael R Edwards and Sebastian L Johnston http://dx.doi.org/10.1002/emmm.201100143 The paper explained PROBLEM: IL-28 cytokines or type III interferons exhibit potent antiviral and anticancer function. However, their full spectrum of activities in the immune system and their role in the context of an inflammatory disease remain poorly understood. This is despite recent evidence linking low levels of IL-28 cytokines with the severity of inflammation in asthma and viral exacerbations of asthma. RESULTS: Using IL-28Rα−/− mice, IL-28A gene transfer, recombinant IL-28A administration and an established model of experimental asthma in mice, we reveal a key function of IL-28 cytokines in inducing type 1 immunity and protecting from allergic airway disease. Abrogation of endogenous IL-28 function in IL-28Rα−/− mice augmented Th2 and Th17 responses as well as IgE levels and exacerbated allergic airway inflammation. In contrast, IL-28A treatment promoted Th1 responses, suppressed Th2 and Th17 responses and ameliorated allergic airway disease. This was due to IL-28A-mediated modulation of conventional DC function inducing IL-12p70 production and Th1 differentiation. IMPACT: This work extends our current knowledge on the mechanisms regulating allergic responses in the airways, provides new insight about the role of IL-28 cytokines in adaptive immunity and strengthens the rationale for the therapeutic administration of IL-28A in allergic asthma and related allergic diseases in humans. INTRODUCTION Allergic asthma is due to the failure of the immune system to develop tolerance to otherwise innocuous environmental aeroallergens (Holgate & Polosa, 2008). As a result, inappropriate Th2-mediated immune responses are induced that orchestrate the asthmatic response by promoting the production of IgE, the infiltration of lymphocytes and eosinophils, and the induction of airway inflammation and hyper-responsiveness (Umetsu & DeKruyff, 2006). Aeroallergen-directed Th17 responses can further contribute to this process by triggering the infiltration of neutrophils and the hyper-secretion of mucus (Holgate & Polosa, 2008). To prevent this from happening, the host employs a multitude of often complementary regulatory mechanisms that include the generation of Th1-specific immune responses that cross-regulate Th2 responses to allergen and/or the induction of regulatory T cell responses. The rate-limiting step in the generation of Th2-mediated allergic responses in the lung, and the induction of counter-regulatory Th1 or Treg responses, is the presentation of allergen by local DCs (van Rijt et al, 2005). This is influenced by the lung microenvironment and the presence of allergic or infectious insults that trigger the expression of key inflammatory cytokines such as thymic stromal lymphopoietin (TSLP) and IL-12 that modulate DC function and promote Th2 or Th1 cell differentiation, respectively. Still, the majority of factors responsible for controlling DC-mediated T helper cell polarization, especially in the context of allergic disease, remain incompletely understood. Recently, a new family of cytokines known as interleukins-28/29, λ-interferons or type III interferons (IFN) was discovered. IL-28/29 cytokines represent an interesting evolutionary link between type I IFNs and the IL-10 family (Kotenko et al, 2003; Sheppard et al, 2003; Siren et al, 2005). They consist of three members in humans, denoted IL-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1), and two members in mice (IL-28A and IL-28B) (Lasfar et al, 2006), all of which signal through a heterodimeric receptor consisting of IL-28Rα (IFN-λR1 or CRF2-12) responsible for ligand specificity, and IL-10Rβ (IL-10R2 or CRF2-4) shared with all other IL-10 family members. Although IL-10Rβ is ubiquitously expressed, IL-28Rα expression is restricted to cells of epithelial derivation including hepatocytes and myeloid lineage cells such as dendritic cells (DCs) and macrophages (Doyle et al, 2006; Mennechet & Uze, 2006). IL-28 cytokine family members are produced by various cells including antigen presenting cells upon viral infection or Toll like receptor ligation (Doyle et al, 2006; Lauterbach et al, 2010; Siebler et al, 2007; Siren et al, 2005). It is now well established that IL-28 cytokines exhibit potent antiviral and anti-cancer activity. They inhibit viral replication (Robek et al, 2005), they up-regulate cytotoxic responses to virally infected cells (Ank et al, 2008) and they reduce tumour growth and metastases in mice (Numasaki et al, 2007). More recently, additional activities of IL-28 cytokine family members in the immune system have been suggested. For instance, IL-29-treated DCs induce proliferation of FoxP3-expressing regulatory T cells in vitro (Mennechet & Uze, 2006), whereas addition of IL-29 to human PBMC or T cell cultures in vitro inhibits the production of IL-5 and IL-13 (Dai et al, 2009; Jordan et al, 2007; Srinivas et al, 2008). Moreover, transgenic expression of IL-28A in vivo promotes the induction of Th1 over Th2 responses and the severity of ConA-induced liver injury (Siebler et al, 2007). In humans, a strong link between low expression of IL-28 cytokines and severity of allergic asthma and allergic asthma exacerbations has been described. Asthmatic patients exhibit deficient induction of IL-28 and IL-29 in response to rhinovirus infection, and deficient IL-28/29 expression correlates with the severity of rhinovirus-induced asthma exacerbations and virus load in experimentally infected human volunteers (Contoli et al, 2006). Moreover, in the absence of detectable viral infection asthmatic patients with active disease still exhibit an inverse correlation between IL-28 and IL-29 mRNA levels and severity of the allergic response in the airways (Bullens et al, 2008). This raises the possibility that in addition to their role in antiviral immunity IL-28 cytokines may also modulate adaptive immune responses that underlie the pathogenesis of asthma. Here, we demonstrate that IL-28A promotes Th1 cell differentiation in vivo and suppresses Th2-mediated responses in the airways, and we identify IL-28 cytokines as new immunotherapeutic agents for the treatment of allergic airway disease. RESULTS Overexpression of IL-28A in the lung inhibits Th2 and Th17 responses and suppresses allergic airway disease To explore the role of IL-28 cytokines in allergic airway disease, we used an established mouse model of allergen sensitization and challenge (Fig 1A). We first investigated the expression of IL-28A and IL-28B (97% identical in amino acid sequence) in the bronchoalveolar lavage fluid (BALF) during the development of allergic airway inflammation and found that, similarly to human patients, IL-28 cytokines were expressed at only low levels (Fig 1B). To up-regulate IL-28 levels and examine whether this has functional consequences in disease development, we constructed a recombinant replication-deficient adenovirus expressing IL-28A under control of the CMV promoter (AdIL-28) and applied it to the lung. This resulted in high levels of IL-28A production in the BALF of treated mice (Fig 1B), which profoundly impacted on allergic airway disease. We found that AdIL-28 but not Ad0 or vehicle control treatments significantly reduced eosinophil, neutrophil and lymphocyte cell numbers in the BALF (Fig 1C–D) and leukocyte infiltration in the perivascular and peribronchial areas of the lung (Fig 1E). This was accompanied by significantly decreased goblet cell metaplasia and hyper-secretion of airway epithelial mucus in the lung of AdIL-28-treated mice compared to controls (Fig 1F). Notably, effector Th2 and Th17 responses to OVA were also suppressed as demonstrated by the inhibition of IL-5, IL-10, IL-13 and IL-17 in the lung-draining mediastinal lymph nodes (MLNs), whereas the Th1 cytokine IFN-γ was up-regulated (Fig 1G). In contrast, IL-4 was not detectable in this assay (data not shown). Finally, protection from airway hyper-responsiveness (AHR) measured as metacholine-induced increases in total lung resistance was observed in mice treated with AdIL-28, whereas mock adenovirus (Ad0) or vehicle administration (PBS) had no effect (Fig 1H). Collectively, these findings demonstrate that high IL-28A levels in the lung effectively suppress the development of Th2 and Th17 cell mediated inflammatory responses and Th2-mediated allergic airway disease. Figure 1. Adenoviral expression of IL-28A during allergen challenge suppresses the development of allergic airway disease. A.. Experimental protocol. C57BL/6 mice were subjected to vehicle (PBS), mock (Ad0) or IL-28A expressing adenovirus (AdIL-28) treatment in the lung and then challenged with aerosolized OVA (OVA/OVA) or PBS (PBS/PBS). B.. Total IL-28 levels in the BALF of lungs from PBS or OVA-sensitized and challenged mice in the presence of AdIL-28, Ad0 or PBS treatment. For the analysis of IL-28 levels, BALF was concentrated 10X as detailed in Materials and Methods section. Results are expressed as mean values ± SEM of 4–8 mice per group from two independent experiments. C.. BALF differential counts for eosinophils and neutrophils expressed as mean ± SEM of 10–14 mice per group from three independent experiments are shown. D.. BALF differential counts for lymphocytes expressed as mean ± SEM of 10–14 mice per group from three independent experiments are shown. E.. Histological assessment of lung inflammation in AdIL-28-treated mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from 10 mice per group are shown. F.. Histological assessment of mucus secretion in AdIL-28-treated mice. Periodic acid Schiff (PAS)-stained sections and morphometric analysis expressed as mean values ± SEM from 10 mice per group are shown. G.. Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels in supernatants of OVA-stimulated MLN cultures expressed as mean values ± SEM of five mice per group are shown. Data are representative of two independent experiments. H.. AHR measured as metacholine-induced increases in total lung resistance (RL) in mechanically ventilated mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM of eight mice per group from two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001. Download figure Download PowerPoint Intranasal administration of recombinant IL-28A effectively treats allergic airway disease in mice Subsequently, we examined whether recombinant IL-28A (IL-28A) administered intranasally during OVA challenge (Fig 2A) would also be capable of suppressing Th2-mediated allergic airway disease and thus whether it could be therapeutically useful. Indeed, we found that IL-28A treatment effectively suppressed the number of eosinophils and neutrophils in the BALF (Fig 2B) although it had no effect on the number of lymphocytes (Fig 2C). IL-28A treatment also inhibited the infiltration of leukocytes in the lung (Fig 2D) and led to the reduction of goblet cell metaplasia (Fig 2E). Notably, IL-28A-mediated suppression of disease severity was accompanied by a significant inhibition of IL-5, IL-13 and IL-17 in lung-draining MLNs and a marked up-regulation of IFN-γ (Fig 2F). Similar inhibition of Th2 and Th17 responses was also observed in purified lung CD4+ T cells from IL-28A treated mice (Supporting Information Fig S1A–B). Finally, IL-28A treatment ameliorated lung function by reducing AHR in response to increasing doses of MCh (Fig 2G). These data support a potent therapeutic effect of recombinant IL-28A treatment in allergic airway disease. Figure 2. Treatment with recombinant IL-28A suppresses Th2/Th17 cytokine production and ameliorates allergic airway disease. A.. Experimental protocol. BALB/c mice were challenged for three consecutive days with inhaled OVA in the absence (OVA/OVA + PBS) or presence of recombinant IL-28A (OVA/OVA + IL-28A). Control mice were challenged with PBS (PBS/PBS). B.. BALF differential counts for eosinophils and neutrophils expressed as mean ± SEM of 3–4 mice per group. One representative of two independent experiments is shown. C.. BALF differential counts for lymphocytes expressed as mean ± SEM of 3–4 mice per group. One representative of two independent experiments is shown. D.. Histological assessment of lung inflammation in IL-28A-treated mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from six mice per group are shown. E.. Histological assessment of mucus secretion in IL-28A-treated mice. PAS stained sections and morphometric analysis expressed as mean values ± SEM from six mice per group are shown. F.. Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels are expressed as mean values ± SEM in supernatants of OVA-stimulated MLN cultures of 10–12 mice per group from two independent experiments. G.. AHR measured as metacholine-induced increases in total lung resistance (RL) in anesthetized BALB/c mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM of five mice per group. One representative of three independent experiments is shown. *p < 0.05; **p < 0.01; ***p < 0.001. Download figure Download PowerPoint IL-28Rα−/− mice exhibit augmented Th2 and Th17 responses and exacerbated allergic airway inflammation To explore the role of endogenous IL-28 cytokine production in allergic airway disease, we took advantage of mice in which the IL-28RA gene encoding the alpha chain of the IL-28 receptor complex has been inactivated by homologous recombination (Ank et al, 2008). Using the OVA model of allergic airway inflammation (Fig 1A), we found that OVA-sensitized and -challenged IL-28Rα−/− mice exhibited a significant increase in eosinophilic cell infiltration in the BALF as compared to wild-type controls (Fig 3A, left panel). Although eosinophils constituted the main infiltrating cell population in the lung, an increase in neutrophils (Fig 3A, right panel) and a tendency for increased lymphocytes (Fig 3B) was also observed in IL-28Rα−/− mice. This was further accompanied by significantly enhanced inflammatory infiltrates in the lung (Fig 3C) and goblet cell metaplasia in the airways (Fig 3D) of IL-28Rα−/− mice. Notably, effector Th2 and Th17 cell responses against OVA were also increased in IL-28Rα−/− mice. MLN cells from IL-28Rα−/− mice exhibited significantly higher levels of IL-5, IL-13 and IL-17 than their wild-type counterparts whereas IFN-γ levels were very low, due to the strong Th2 skewing of this model, and not affected (Fig 3E). Similar observations were also made when CD4+ T cells from the lung of IL-28Rα−/− mice were analysed (Supporting Information Fig S2A–C). Although IL-4 was not detectable in MLN cultures, it was readily produced in CD4+ T cell cultures from the lung and significantly up-regulated in IL-28Rα−/− mice (Supporting Information Fig S2A). Finally, IL-28Rα−/− mice exhibited increased IgE levels in the serum compared to wild-type controls (Fig 3F). Figure 3. IL-28Rα-deficient mice develop increased Th2/Th17 responses and Th2/Th17-mediated allergic airway inflammation. A.. BALF differential counts of eosinophils and neutrophils expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown. B.. BALF differential counts of lymphocytes expressed as mean ± SEM of 3–4 mice per group. One representative from three independent experiments is shown. C.. Histological assessment of lung inflammation in IL-28Rα+/+ and IL-28Rα−/− mice. Hematoxylin and eosin stained lung sections and histological scoring expressed as mean values ± SEM from 5 to 7 mice per group are shown. D.. Histological assessment of mucus secretion in IL-28Rα+/+ and IL-28Rα−/− mice. PAS stained sections and morphometric analysis expressed as mean values ± SEM from 5 to 7 mice per group are shown. E.. Effector T cell responses in MLNs of OVA sensitized and challenged mice. Cytokine levels in supernatants of OVA-stimulated MLN cultures expressed as mean values ± SEM of seven mice per group from two independent experiments are shown. F.. Increased total IgE levels in the serum of IL-28Rα−/− mice as compared to IL-28Rα+/+ littermates after OVA sensitization and challenge. Data represent mean values ± SEM. G.. AHR measured as metacholine-induced increases of total lung resistance (RL) in mechanically ventilated IL-28Rα+/+ and IL-28Rα−/− mice. Data are expressed as mean values of percentage increase from baseline of the total RL ± SEM from 10 mice per group pooled from two independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001. Download figure Download PowerPoint In contrast, AHR of OVA-sensitized and challenged IL-28Rα−/− mice was only marginally affected at saline and low MCh doses but not thereafter (Fig 3G), suggesting the influence of additional non-inflammatory parameters to this response. Indeed, remodelling changes such as increased collagen deposition around the bronchi were also observed in IL-28Rα−/− mice (Supporting Information Fig S2D). Taken together, these data indicate that endogenously produced IL-28 cytokines are involved in damping down allergic airway inflammation and mucus hyper-secretion in mice. IL-28 cytokines drive Th1 differentiation in vivo Inhibition of effector Th2 responses and induction of IFN-γ seem to be central to IL-28A-mediated suppression of allergic airway disease. To get insight into this process, we examined the ability of IL-28 cytokines to modulate T helper cell differentiation during a primary immune response in vivo. We found that during primary immunization with OVA in alum, IL-28Rα−/− mice developed markedly enhanced Th2 and Th17 responses to OVA than their wild-type counterparts characterized by increased production of IL-4, IL-5, IL-13 and IL-17 (Fig 4A). At the same time, IL-28Rα−/− mice exhibited impaired IFN-γ production in response to OVA (Fig 4B) or the immunodominant CD4+ T cell specific OVA peptide OT-II (Fig 4C), suggesting that endogenous IL-28 cytokines (IL-28A and/or IL-28B) are critically involved in promoting CD4+ T cell differentiation to a Th1 phenotype. IL-28-induced Th1 cell differentiation appears to be a general aspect of the biology of IL-28 cytokines as mice immunized with OVA emulsified in Complete Freud's adjuvant (OVA/CFA), a potent Th1-inducing adjuvant, also exhibited reduced Th1 and enhanced Th2 responses to OVA (Supporting Information Fig S3A–B). On the contrary, IL-28A overexpression during primary immunization with OVA in alum exerted exactly the opposite effect by increasing IFN-γ and reducing IL-5, IL-13 and IL-17 production (Fig 4D). Taken together, these findings suggest that IL-28 cytokines act as inhibitors of Th2 and Th17 cell differentiation by favouring Th1 responses in vivo. Figure 4. IL-28 signalling is required for skewing T helper cell differentiation to a Th1 cytokine profile. A.. Primary Th2 cell responses in OVA/alum immunized IL-28Rα+/+ and IL-28Rα−/− mice 6 days post-immunization. Cytokine levels in supernatants of OVA-stimulated splenocyte cultures expressed as mean values ± SEM of five mice per group are shown. One representative of two independent experiments is shown. B.. Primary Th1 cell responses in OVA/alum immunized IL-28Rα+/+ and IL-28Rα−/− mice 6 days post-immunization. Levels of IFN-γ in supernatants of OVA-stimulated splenocyte cultures expressed as mean values ± SEM of five mice per group are shown. One representative of two independent experiments is shown. C.. IFN-γ production from CD4+ and CD8+ T cells of OVA/alum immunized IL-28Rα+/+ and IL-28Rα−/− mice 6 days post-immunization. Levels of IFN-γ in supernatants of OT-II and OT-I-stimulated splenocyte cultures expressed as mean values ± SEM of five mice per group are shown. One representative of two independent experiments is shown. D.. Effect of IL-28A expressing adenovirus (AdIL-28) treatment on primary Th2 cell responses of OVA/alum immunized C57BL/6 wild-type mice. AdIL-28, Ad0 or vehicle control (PBS) were administered to mice 1 day pre-immunization and T cell responses assessed 6 days post-immunization. Cytokine levels in supernatants of OVA-stimulated splenocyte cultures expressed as mean values ± SEM of five mice per group are shown. One representative of two independent experiments is shown. *p < 0.05; **p < 0.01; ns, non-significant. Download figure Download PowerPoint IL-28A reprograms lung DCs to promote type 1 responses and inhibit Th2 cell development in vivo To understand how IL-28A controls T helper cell differentiation and Th2-mediated allergic airway disease, and explain the strong Th1-polarizing capacity of IL-28A in vivo, we assessed the expression of IL-28Rα on lung immune cells. Using cell sorting and quantitative PCR, we found that lung CD11c+ DCs and cultured bone marrow derived DCs expressed high levels of IL-28Rα mRNA (Fig 5A). Consistently, alveolar macrophages and DC-like cells present in the lung parenchyma stained positive for IL-28Rα protein" @default.
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• W1834477603 title "IL‐28A (IFN‐λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease" @default.
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