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R. Zhou, R. Rigden, R. Horai, R. Villasmil, R. Caspi; Dual Function for a Vision Related Molecule: Retinoic Acid in the Eye May Contribute to Ocular Immune Privilege. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1170.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular immune privilege encompasses both local and systemic mechanisms. Retinoic acid (RA) is abundant in the eye as it participates in the chemistry of vision. RA is involved in immune regulation at mucosal surfaces but its role, if any, in immune responses involving the eye has not been studied. We therefore examined ocular fluids for immunoregulatory activity that could be attributed to RA.
Purified CD4+ T cells were activated with anti-CD3/CD28 in the presence or absence of aqueous humor (AH), under neutral or polarizing conditions. Cell proliferation was determined by [3H]-thymidine incorporation assay. Detection of cytokines and cellular receptors was by flow cytometry, confocal microscopy and/or real-time PCR.
RA-synthesizing enzymes RALDH1, 2 and 3 were expressed in the cornea and retina. AH added to T cells undergoing stimulation under Th1 or Th17 polarizing conditions inhibited proliferation and acquisition of effector function, as demonstrated by reduction of IFNγ and IL-17, and instead caused their massive conversion into FoxP3+ Tregs. AH reduced expression of CTLA-4, GITR, CD25 and CD103 on conventional, but not on the Foxp3+ T cells, and downregulated expression of molecules involved in Th17 responses, including IL-17, IL-21, IL-22, RORγt and IL-23R (but not IL-6R). The activity of AH involved TGFβ-driven upregulation of RARα and could be reversed by antagonizing either RA or TGFβ, using LE540 or anti-TGFβ antibodies, respectively. In contrast to T cells undergoing initial activation in presence of AH, previously activated cells exposed to AH on 2nd stimulation were resistant to effects of AH. IRBP T cell receptor transgenic cells injected into the eyes of live mice converted from FoxP3- to FoxP3+ cells in vivo.
The role of RA in the eye is not limited to the visual process but also contributes to ocular immune privilege. Nevertheless, differentiated effector cells are relatively insensitive to AH, helping to explain occurrence of uveitis in the face of an inhibitory ocular microenvironment. Conversion of conventional to FoxP3+ T cells within the eye occurs in vivo and may regulate intraocular inflammation.
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