Conversion of conventional T cells to Tregs within the eye and the dual role of the vision related molecule, retinoic acid, in ocular immune privilege (48.1)

Abstract

Abstract Ocular immune privilege protects the eye from immune damage in part through TGFβ. Retinoic acid (RA) is abundant in the eye, as it participates in the chemistry of vision. However, its role, if any, in immune responses involving the eye is unknown. RA-synthesizing enzymes RALDH1, 2 and 3 were expressed in the cornea and retina. Aqueous humor (AH) massively induced Foxp3 expression in purified CD4+ T cells stimulated through the T cell receptor, while suppressing their proliferation and acquisition of effector function, as judged by reduction of lineage-specific transcription factors and effector cytokines for Th1, Th2 and Th17. AH-induced Foxp3+ T cells expressed CD25, GITR, CTLA4, CD103 and were functionally suppressive. The effect of AH was reversed by antagonizing either RA or TGFβ signaling and involved TGFβ-driven upregulation of RARα. Foxp3 expression was reduced upon removal of AH from culture, but was stabilized by the DNA demethylating agent 5-AZA. Importantly, naive retina-specific (but not polyclonal) T cells, injected into the eyes of live mice, were converted in vivo into Foxp3+ cells. In contrast, previously primed T cells exposed to AH on 2nd stimulation were resistant to suppressive effect of AH. Thus, RA in the eye plays a dual role: in vision and in immune privilege, by local induction of Tregs. However, primed effector cells are relatively insensitive to AH, helping to explain occurrence of uveitis in the face of an inhibitory ocular microenvironment.