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Ru Zhou, Reiko Horai, WaiPo Chong, Carlos Rodrigo Zarate-Blades, Jun Chen, Phyllis B. Silver, Rachel R. Caspi; Vitamin A Deficiency Hinders The Development Of Experimental Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2939.
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An active metabolite of vitamin A (VitA), all-trans retinoic acid (ATRA), can synergize with TGF-beta to induce Foxp3+ regulatory T cells (Treg) and inhibit IL-17-producing Th17 cells. Others reported that augmentation of VitA by treatment with ATRA or its receptor-specific agonist reduces inflammation in experimental autoimmune uveitis (EAU) at least in part by enhancing Treg cells. We therefore hypothesized that systemic depletion of VitA will inhibit Treg induction and enhance disease.
To generate VitA deficient (VAD) mice, pregnant B10.RIII females were fed a VitA deficient diet from day 14 of gestation. Pups continued to be maintained on the same diet. To assess intraocular Treg conversion, IRBP-specific naïve T cells were injected into eyes of VAD mice. In vitro, CD4+ T cells were activated under neutral or Th1-, Th17-polarizing conditions. In vivo, VAD mice were immunized with the uveitogenic peptide IRBP161-180. Expression of Foxp3, IL-17, or IFN-γ in CD4+ T cells were assessed by intracellular staining. Cell proliferation was detected by 3H-thymidine uptake. Cell culture supernatants were assayed for IL-17 and IFN-γ by ELISA.
Surprisingly, VAD mice were resistant to EAU induction. Compared to mice fed control diet, VAD mice had significantly reduced conversion of conventional T cells to FoxP3+ Tregs locally in the eye but, unexpectedly, they showed a higher ratio of FoxP3+ Treg to T effector CD4+ T cells in the periphery. Proliferation to IRBP in vitro of whole lymph node cells from IRBP-immunized VAD mice was not reduced, but Ag specific production of IL-17 and IFN-γ were drastically diminished.
Despite defective Treg conversion in the eye, VAD mice still have peripheral Tregs. Reduction in Th1 and Th17 responses without reduction of Ag specific proliferation suggest that resistance of VAD mice to EAU may reflect a defect in effector T cell generation under conditions of VitA deficiency that is unconnected to inhibition by Tregs.
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