title: Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells.
abstract: BACKGROUND
  We previously reported that the peripheral regulatory T cells (pTregs) generated 'on-demand' in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs). Here, we expanded these findings by examining whether locally generated, locally acting pTregs were protective against spontaneous autoimmunity and autoimmunity mediated by interphotoreceptor retinoid-binding protein (IRBP). We also examined the APC capacity of retinal DC in vivo.
  
  
  METHODS
  Transgenic (Tg) mice expressing diphtheria toxin receptor (DTR) and/or green fluorescent protein (GFP) under control of the endogenous FoxP3 promoter (GFP only in FG mice, GFP and DTR in FDG mice) or the CD11c promoter (GFP and DTR in CDG mice) were used in conjunction with Tg mice expressing beta-galactosidase (βgal) as retinal neo-self antigen and βgal-specific TCR Tg mice (BG2). Retinal T cell responses were assayed by flow cytometry and retinal autoimmune disease assessed by histological examination.
  
  
  RESULTS
  Local depletion of the Tregs enhanced actively induced experimental autoimmune uveoretinitis to the highly expressed retinal self-antigen IRBP in FDG mice and spontaneous autoimmunity in βgal-FDG-BG2 mice, but not in mice lacking autoreactive T cells or their target antigen in the retina. The presence of retinal βgal downregulated the generation of antigen-specific Teffs and pTregs within the retina in response to local βgal challenge. Retinal DC depletion prevented generation of Tregs and Teffs within retina after βgal injection. Microglia remaining after DC depletion did not make up for loss of DC-dependent antigen presentation.
  
  
  CONCLUSIONS
  Our results suggest that local retinal Tregs protect against spontaneous organ-specific autoimmunity and that T cell responses within the retina require the presence of local DC.
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Rm, 310, Lion's Research Bldg,,2001 6th St, SE,, Minneapolis 55455-3007, Minnesota, USA. mcphe003@umn.edu.
authors.forename: Scott W
authors.initials: SW
authors.lastname: McPherson
authors.forename: Neal D
authors.initials: ND
authors.lastname: Heuss
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Pierson
authors.forename: Dale S
authors.initials: DS
authors.lastname: Gregerson
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005136:Eye Proteins / Q000276:immunology*; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D012160:Retina / Q000276:immunology*; D012177:Retinol-Binding Proteins / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D001324:Autoantigens; D005136:Eye Proteins; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial