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Phyllis B. Silver, Reiko Horai, Jun Chen, Anna M. Hansen, William McManigle, Rafael Villasmil, Rachel R. Caspi; T regulatory Cells Accumulate in the Eye During Uveitis and Act to Control Inflammation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4765.
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© ARVO (1962-2015); The Authors (2016-present)
Autoimmune disease can occur when peripheral T regulatory cells (Tregs) are unable to maintain self-tolerance. Tregs are found in eyes of mice with IRBP-induced experimental autoimmune uveitis (EAU). We examined whether Tregs in uveitic eyes are specific for IRBP, whether they are functionally suppressive, and whether they play a role in recovery.
B10.RIII mice expressing a FoxP3-GFP reporter gene were immunized with IRBP161-180 to induce EAU. Eyes were collected at different time points. Disease was confirmed by fundoscopy. IRBP-specific T cells were detected with fluorescently labeled IRBP-MHC class II dimers by flow cytometry. Sorted eye-derived Tregs were examined for ability to suppress proliferation of (i) naïve IRBP-specific T cells (from IRBP T cell receptor transgenic Rag-/- donors) or (ii) antigen-experienced effector T cells sorted from uveitic eyes. DEREG mice, which express diphtheria toxin receptor under control of the FoxP3 promoter, were utilized to determine how the depletion of Tregs affects disease resolution.
During EAU, Tregs infiltrate inflamed eyes and progressively increase in proportion to T effector cells (Teffs). During peak disease (d 18-21) approximately 20% of FoxP3+ T cells (Tregs) and 40% of FoxP3- T cells (Teffs) in eyes of uveitic mice were IRBP specific by immunofluorescent staining with IRBP-MHC class II dimers. IRBP specific T cells in peripheral lymphoid organs were under the limit of detection. Tregs isolated from eyes of mice with EAU suppressed antigen-specific proliferation of naïve IRBP-specific T cells as well as Teffs from the same uveitic eyes. Importantly, depletion of Tregs from uveitic DEREG mice by injection of diphtheria toxin at peak disease delayed resolution of disease.
The T cell infiltrate in inflamed eyes of mice with IRBP-induced EAU is highly enriched for IRBP-specific Treg and Teff cells. Unlike what has been reported for Tregs in other inflammatory sites, Tregs in the eye are functional and appear to have a role in resolution of disease.
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