title: IL-5-induced hypereosinophilia suppresses the antigen-induced immune response via a TGF-beta-dependent mechanism.
abstract: Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4+ T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-beta1 in the spleen, and we demonstrated that the main cellular source of TGF-beta1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-beta1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4+ T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4+ T cells. Finally, a TGF-beta type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-beta-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakagome
authors.forename: Makoto
authors.initials: M
authors.lastname: Dohi
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.forename: Taku
authors.initials: T
authors.lastname: Kouro
authors.forename: Mitsunobu R
authors.initials: MR
authors.lastname: Kano
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D017681:Hypereosinophilic Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood; D015848:Interleukin-5 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D000941:Antigens; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D016212:Transforming Growth Factor beta; D010047:Ovalbumin