Distinct Programs of Tissue Adaptation Shape Vitreous CD4+ and CD8+ T-cell States in Chronic Uveitis

Abstract

Tissue-resident memory (TRM) T-cells are increasingly recognized as key mediators of chronic autoimmune inflammation, yet their organization and functional adaptation within the eye remain poorly understood. We investigated paired vitreous body biopsies and peripheral blood T cells from patients with chronic posterior segment uveitis using multiparameter flow cytometry, antigen-specific stimulation assays, single-cell RNA sequencing, and T-cell receptor sequencing to define the intraocular tissue-adaptive immune states. Vitreous T cells were phenotypically, transcriptionally, and clonally distinct from their circulating counterparts and enriched for canonical TRM markers. However, tissue adaptation differed substantially between CD4+ and CD8+ lineages. Vitreous CD4+ T cells segregated into clonally expanded tissue-adaptive states characterized by greater CXCR6 expression, enhanced antigen-specific cytokine responses, and well-defined transcriptional profiles. In contrast, vitreous CD8+ T cells expressed higher levels of the retention-associated markers CD103 and CD49a yet maintained greater clonal and phenotypic continuity with peripheral blood T cells. Both vitreous CD4+ and CD8+ subsets exhibited a restrained effector profile associated with tissue-adaptive transcriptional programs. Our data reveal that CD4+ and CD8+ T cells in chronic uveitis assume distinct states in the vitreous microenvironment, such that the intraocular immune response relies on both localized tissue retention and active adaptation to the inflammatory niche.