title: Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis.
abstract: Experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein (IRBP) is a model of human autoimmune uveitis. We examined whether T regulatory cells (Tregs) found in uveitic eyes are IRBP specific, functionally suppressive, and play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3(+) Treg to T effector cell (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Tregs (CD4(+)Foxp3(+)) and up to 60% of Teffs (CD4(+)Foxp3(-)) were IRBP specific, whereas in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teffs from the same eyes. Importantly, systemic depletion of Tregs at peak disease delayed resolution of EAU, and their depletion after resolution triggered a relapse. This could be partially duplicated by depletion of Tregs locally within the eye. Thus, the T cell infiltrate in uveitic eyes of normal mice with a polyclonal T cell repertoire is highly enriched in IRBP-specific Tregs and Teffs. Unlike what has been reported for Tregs in other inflammatory sites, Tregs from uveitic eyes appear unimpaired functionally. Finally, Foxp3(+) Tregs play a role in the natural resolution of uveitis and in the maintenance of remission, which occurs at least in part through an effect that is local to the eye.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Silver
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Phyllis
authors.initials: P
authors.lastname: Silver
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510275, China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Yingyos
authors.initials: Y
authors.lastname: Jittayasothorn
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Flow Cytometry Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Rafael
authors.initials: R
authors.lastname: Villasmil
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Muge R
authors.initials: MR
authors.lastname: Kesen
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; rcaspi@helix.nih.gov.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019175:DNA Methylation; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012008:Recurrence; D012160:Retina / Q000276:immunology* / Q000473:pathology; D012177:Retinol-Binding Proteins / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C498833:Foxp3 protein, mouse