title: Abrogation of Rbpj attenuates experimental autoimmune uveoretinitis by inhibiting IL-22-producing CD4+ T cells.
abstract: Experimental autoimmune uveoretinitis (EAU) is an organ-specific T cell-mediated disease induced by immunizing mice with interphotoreceptor retinoid binding protein (IRBP). Autoaggressive CD4(+) T cells are the major pathogenic population for EAU. We investigated the contribution of Notch signaling in T cells to EAU pathogenesis because Notch signaling regulates various aspects of CD4(+) T cell functions. Rbpj is required for Notch signaling, and Rbpj deficiency in T cells inhibited EAU disease severity. The amelioration of EAU in T cell-specific Rbpj-deficient mice correlated with low levels of IL-22 production from CD4(+) T cells, although IRBP-specific CD4(+) T cell proliferation and Th17 differentiation were unaffected. Administration of recombinant IL-22 during the late phase, but not the early phase, of EAU increased EAU clinical scores in T cell-specific Rbpj-deficient mice. Notch inhibition in mice immunized with IRBP with a γ-secretase inhibitor (GSI) suppressed EAU progression, even when GSI was administered as late as 13 days after IRBP immunization. Our data demonstrate that Rbpj/Notch-mediated IL-22 production in T cells has a key pathological role in the late phase of EAU, and suggest that Notch blockade might be a useful therapeutic approach for treating EAU.
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Zaied Ahmed
authors.initials: ZA
authors.lastname: Bhuyan
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan ; Digestive and Pediatric Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Michihito
authors.initials: M
authors.lastname: Asanoma
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan ; Ophthalmology and Visual Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwata
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishifune
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
authors.affiliation: Digestive and Pediatric Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012173:Retinitis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D012177:Retinol-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism; D014605:Uveitis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D000097043:Interleukin-22; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D007378:Interleukins; D012177:Retinol-Binding Proteins; D000097043:Interleukin-22; D000099214:Retinol-Binding Proteins, Interstitial