Purchase this article with an account.
Reiko Horai, Phyllis B. Silver, Jun Chen, Ru Zhou, Rajeev K. Agarwal, Mary J. Mattapallil, Peng Wang, Chi-Chao Chan, Rachel R. Caspi; Environmental Stimuli Enhance Spontaneous Uveitis Elicited By Retina-specific T Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2953.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
IRBP T cell receptor transgenic (TCR Tg) mice spontaneously develop uveitis. Only activated T cells can enter the eye, but retinal antigens are not available outside the eye to activate them. We dissect IRBP specific responses of these mice to understand where/how T cells specific to retinal antigens are activated and regulated.
IRBP TCR Tg mice were generated on B10.RIII background using TCR constructs from an IRBP161-180 specific T cell line. IRBP-specific T cells were detected using IRBP161-180/I-Ar/IgG1 dimers. T cell markers and intracellular cytokines were analyzed by flow cytometry. Disease was evaluated by fundoscopy and histology. Intestinal flora was depleted with broad-spectrum antibiotics in drinking water.
IRBP TCR Tg mice developed spontaneous uveitis by 2-3 months of age. Most T cells in uveitic eyes had a memory phenotype and included Th1, Th17 and T regulatory cells (Tregs). In contrast, few memory IRBP TCR Tg T cells were present in the periphery. To investigate where priming to sequestered retinal antigens might occur, we treated IRBP TCR Tg mice with broad-spectrum antibiotics to deplete intestinal flora. The antibiotics-treated Tg mice had a drastically altered gut microbial flora and showed a delayed onset and reduced severity of uveitis compared to untreated Tg mice. IRBP-specific Tregs were enriched in uveitic eyes compared to the periphery and were functionally suppressive in vitro to naive T cells. Notably, IRBP-specific "natural" Tregs were absent in the thymus, suggesting that Tregs found in inflamed eyes had been converted from conventional T cells. In line with this, naive IRBP TCR Tg cells injected into eyes of live mice became Foxp3 positive.
IRBP TCR Tg mice provide a platform to study basic mechanisms of immune privilege and pathogenesis of autoimmune uveitis. Our data suggest that even though IRBP is not available in the periphery to prime IRBP-specific T cells, commensal microbiota may provide sufficient activating stimulus to trigger uveitis. Tregs found in the uveitic eye may in part be induced locally, are functionally competent and may limit inflammation.
This PDF is available to Subscribers Only