title: Local "on-demand" generation and function of antigen-specific Foxp3+ regulatory T cells.
abstract: Extrathymically derived regulatory T cells (iTregs) protect against autoimmunity to tissue-specific Ags. However, whether Ag-specific iTreg generation and function is limited to secondary lymphoid tissue or whether it can occur within the tissue-specific local environment of the cognate Ag remains unresolved. Mice expressing β-galactosidase (βgal) on a retina-specific promoter (βgal mice) in conjunction with mice expressing GFP and diphtheria toxin (DTx) receptor (DTR) under control of the Foxp3 promoter, and βgal-specific TCR transgenic (BG2) mice were used to examine this question. Local depletion (ocular DTx), but not systemic depletion (i.p. DTx), of βgal-specific iTregs enhanced experimental autoimmune uveoretinitis induced by activated βgal-specific effector T cells. Injections of small amounts of βgal into the anterior chamber of the eye produced similar numbers of βgal-specific iTregs in the retina whether the mouse was depleted of pre-existing, circulating Tregs. Taken together, these results suggest that protection from tissue-specific autoimmunity depends on the function of local Ag-specific iTregs and that the retina is capable of local, "on-demand" iTreg generation that is independent of circulating Tregs.
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, 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: Dale S
authors.initials: DS
authors.lastname: Gregerson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D007114:Immunization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012160:Retina / Q000276:immunology* / Q000378:metabolism; D012173:Retinitis / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase