Ocular immune privilege in action: The living eye imposes unique regulatory and anergic gene signatures on uveitogenic T cells

Despite ocular immune privilege, circulating retina-specific T cells can trigger autoimmune uveitis, yet intraocular bleeding-a relatively common event-rarely leads to disease. Using an in vivo immune privilege model, we previously reported that all naive retina-specific T cells entering the eye become primed in situ; about 30% become Foxp3⁺ regulatory T cells (Tregs), while the rest fail to induce pathology. Here, single-cell transcriptomics and functional validation revealed distinct phenotypes in both populations: ocular Tregs were highly suppressive, whereas non-Tregs expressed suppression- and anergy-associated genes and lacked regulatory function. Trajectory analyses suggested that Tregs and anergic cells arise from a common proliferative precursor in parallel, rather than sequentially. Our data indicate a key checkpoint governing the divergence of anergic and regulatory fates. These findings provide molecular-level insights into ocular immune privilege and may inform strategies to silence autoimmune effector cells or reverse T cell unresponsiveness in cancer, vaccination, or chronic infection.