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Scott W. McPherson, Neal D. Heuss, Dale S. Gregerson; Local Generation of Regulatory T Cells in the Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6904. doi: https://doi.org/.
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Regulatory T cells (Tregs) are an important component of retinal immune privilege. Here we examine the ability of Tregs to be generated specifically within the retina in response to local antigen (Ag).
FoxP3-DTR/GFP 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 the Ag beta-galactosidase (bgal) and/or mice expressing bgal in photoreceptor cells (arrbgal). Systemic depletion of Treg was done with i.p. injections of diphtheria toxin (DTx). Local Ag injections were done by unilateral anterior chamber (AC) injection of bgal. Tregs were analyzed by FACS on blood or perfused retinas.
Analysis of retinal Tregs in naïve FoxP3-DTR/GFP-BG2 vs. naïve FoxP3-DTR/GFP-BG2-arrbgal mice showed a higher frequency of Ag-specific Tregs in the latter group despite similar overall retinal T cell numbers and percent of Ag-specific Tregs in the blood. AC injection of bgal in FoxP3-DTR/GFP-BG2-arrbgal mice resulted in large increase in Tregs in the ipsilateral retina while the contralateral retina remained at naive levels. Analysis from AC bgal and AC saline injected FoxP3-DT/GFP-BG2 mice showed elevated numbers of Tregs in the ipsilateral retinas of bgal treated mice while contralateral bgal retinas and ipsi- and contralateral saline retinas all had similar low levels of Tregs. Despite a lack of circulating Tregs, FoxP3-DTR/GFP-BG2 mice given systemic DTx followed by AC bgal injection developed similar significant populations of retinal Tregs retinas as mice receiving only AC bgal. Control mice receiving no Dtx and no AC bgal as well as mice receiving only DTx had very few retinal Tregs.
Our data suggests that retinal Ag, whether constitutive or introduced by local injection, can induce the production of Tregs from mature, circulating, FoxP3- precursor T cells. Our findings that Treg levels only differed in Ag injected ipsilateral retinas, or only in the retinas of mice with constitutive Ag expression, suggest that the production of Tregs occurs within the retina.
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