A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid

摘要

The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-γ production and generation of T regulatory cells (Treg) 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 naïve T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted their massive conversion to FoxP3⁺ Treg 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 RARα. Newly converted FoxP3⁺ Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-AZA. 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.