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Scott McPherson, Neal Heuss, Mark Pierson, Dale Gregerson; Local Regulatory T Cells of the Retina Protect Against Spontaneous and Induced Autoimmune Disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2030. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Previously we showed that local depletion of regulatory T cells (Tregs) from the retina enhanced autoimmune disease against beta-galactosidase (bgal) expressing photoreceptor cells induced by activated, bgal-specific T cells (McPherson, et. al., ARVO 2012 and manuscript submitted). Here we examine whether retinal Tregs 1) limit interphotoreceptor retinoid-binding protein (IRBP) induced autoimmunity and 2) protect against spontaneous retinal autoimmunity.
FDG mice, which express green fluorescent protein (GFP) and diphtheria toxin receptor (DTR) under control of the FoxP3 promoter, were used to track and/or deplete Tregs. These mice were also crossed with T cell receptor transgenic mice (BG2) specific for bgal and/or mice expressing bgal in photoreceptor cells (bgal mice). IRBP-mediated autoimmune disease was induced in FDG mice by immunization with IRBP peptides. Local (retinal) depletion of Tregs was done with anterior chamber (AC) injections of diphtheria toxin (DTx). Systemic depletion of Treg was done with i.p. injections of DTx. Tregs were analyzed by FACS on blood or perfused retinas. Retinal autoimmune disease was analyzed by histology.
IRBP immunized FDG mice were given regular AC injections of DTx in the right eye, (3x per week) and occasional injections in the left eye (day 5, day 8, or day 5 and 8). Examination of eyes 21 days post immunization showed elevated incidence and severity of autoimmune disease in the right eyes compared to either the left eyes and eyes from immunized only mice, which were similar. Spontaneous retinal autoimmune disease developed more often in otherwise naive and healthy FDG-BG2-bgal mice given regular AC DTx injections compared to similarly treated naïve FDG, FDG-BG2, or FDG-bgal mice. Conversely, when given systemic DTx, none of the mice develop retinal autoimmunity despite having systemic autoimmune symptoms.
Tregs are an important component of retinal immune privilege. We found that only that sustained local depletion of Tregs enhanced retinal autoimmunity whether induced or spontaneous. This suggests that Tregs within the retina act locally to maintain retinal immune homeostasis.
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