title: A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid.
abstract: The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-γ production, and generation of regulatory T cells (Tregs) by aqueous humor (AH) and identified TGF-β as a critical factor. However, T cell subsets including Foxp3(+) Treg and Th17 were unknown at that time, as was the role of retinoic acid (RA) in Treg induction. Consequently, the effect of the ocular microenvironment on T cell lineage commitment and function, and the role of RA in this process, had not been explored. We now use gene-manipulated mice and highly purified T cell populations to demonstrate that AH suppresses lineage commitment and acquisition of Th1 and Th17 effector function of naive T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted its massive conversion to Foxp3(+) Tregs that expressed CD25, GITR, CTLA-4, and CD103 and were functionally suppressive. TGF-β and RA were both needed and synergized for Treg conversion by AH, with TGF-β-enhancing T cell expression of RA receptor α. Newly converted Foxp3(+) Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-aza-2'-deoxycytidine. In contrast, T cells already committed to effector function were resistant to the suppressive and Treg-inducing effects of AH. We conclude that RA in the eye plays a dual role: in vision and in immune privilege. Nevertheless, primed effector T cells are relatively insensitive to AH, helping to explain their ability to induce uveitis despite an inhibitory ocular microenvironment.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Zhou
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Mattapallil
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D005123:Eye / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D014212:Tretinoin / Q000276:immunology* / Q000378:metabolism
chemical_list: D014212:Tretinoin