April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Environmental Stimuli Enhance Spontaneous Uveitis Elicited By Retina-specific T Cells
Author Affiliations & Notes
  • Reiko Horai
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Phyllis B. Silver
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Jun Chen
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Ru Zhou
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Rajeev K. Agarwal
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Mary J. Mattapallil
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Peng Wang
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Chi-Chao Chan
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Rachel R. Caspi
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  Reiko Horai, None; Phyllis B. Silver, None; Jun Chen, None; Ru Zhou, None; Rajeev K. Agarwal, None; Mary J. Mattapallil, None; Peng Wang, None; Chi-Chao Chan, None; Rachel R. Caspi, None
  • Footnotes
    Support  NIH Intramural grant
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2953. doi:
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      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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: uveitis-clinical/animal model • immune tolerance/privilege • immunomodulation/immunoregulation 
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