title: Alloantigen-specific CD4(+) regulatory T cells induced in vivo by ultraviolet irradiation after alloantigen immunization require interleukin-10 for their induction and activation, and flexibly mediate bystander immunosuppression of allograft rejection.
abstract: Ultraviolet (UV) irradiation prior to antigen immunization is employed to induce antigen-specific regulatory T cells (Tregs). UV-induced Tregs demonstrate unique bystander suppression, although antigen-specific activation is required initially. We previously reported the phenotype of alloantigen-specific transferable Tregs induced by UV-B irradiation after immunization was the same as T regulatory type 1-like CD4(+) T cells, with antigen-specific interleukin (IL)-10 production. Here, by using semi-allogeneic transplantation models in vivo, we investigated the role of IL-10 in the induction and activation of these Tregs, and the possibility of bystander suppression of third-party allograft rejection. Naïve mice (H-2(b)) were immunized with alloantigen (H-2(b/d)), and received UV-B irradiation (40 kJ/m(2)) 1 week later. Four weeks afterwards, splenic CD4(+) T cells were purified from the UV-irradiated immunized mice, and were transferred into naïve mice (H-2(b)). Allografts expressing the same alloantigen as T-cell donors were immunized against (H-2(b/d)) or an irrelevant alloantigen (H-2(b/k)) were transplanted to CD4(+) T-cell-transferred mice, and an alloantigen-specific prolongation of allograft survival observed. Experiments where IL-10 was neutralized by monoclonal antibody in the induction or effector phase revealed that IL-10 is critical, not only for induction but also for immunosuppressive function of CD4(+) Tregs induced by UV irradiation after alloantigen immunization. Third-party allografts (H-2(d/k)) were transplanted to CD4(+) T-cell-transferred mice, and graft survival was also prolonged. Even a graft only partially compatible with immunized alloantigen worked well in vivo to activate CD4(+) Tregs induced by UV irradiation after alloantigen immunization, which resulted in the bystander suppression of third-party allograft rejection.
authors: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan; Department of Hepato-pancreato-biliary and Transplant Surgery, Kyoto University Hospital, Kyoto, Japan. Electronic address: horit@kuhp.kyoto-u.ac.jp.
authors: Tomohide
authors: T
authors: Hori
authors: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: Kagemasa
authors: K
authors: Kuribayashi
authors: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan; Department of Hematology and Medical Oncology, Mie University Hospital, Tsu, Japan.
authors: Kanako
authors: K
authors: Saito
authors: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: Linan
authors: L
authors: Wang
authors: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: Mie
authors: M
authors: Torii
authors: Department of Hepato-pancreato-biliary and Transplant Surgery, Kyoto University Hospital, Kyoto, Japan.
authors: Shinji
authors: S
authors: Uemoto
authors: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan. Electronic address: katotaku@doc.medic.mie-u.ac.jp.
authors: Takuma
authors: T
authors: Kato
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002450:Cell Communication; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation; D007114:Immunization; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D019138:Antibodies, Blocking; D007519:Isoantigens; D016753:Interleukin-10
keywords: Allograft rejection; Bystander immunosuppression; Interleukin-10; Regulatory T cells; Ultraviolet