Clonally Expanded T Cells Reveal a Pathophysiologic Distinction Between Disease Subtypes in Human Uveitis

Abstract Text: Uveitis is a heterogeneous group of inflammatory eye diseases leading to blindness. Lack of pathophysiologic understanding underlies the failure of empiric treatment for 30-60% of patients. We used single cell RNA and V(D)J sequencing to study ocular immune cells in aqueous biopsies from 23 uveitis patients. We found evidence of antigen-driven immune responses in uveitis including clonal expansion of ocular lymphocytes. The most highly expanded T cells shared a core gene signature that included CXCR6, HOPX, LGALS1/3 and IFNG and lacked SELL, TCF7 and CCR7, consistent with antigen-driven T cell activation. Highly expanded CD4 T cells were specifically enriched in RORA and IFNG with lower levels of RORC and IL17F, corroborating murine studies that suggest Th1 responses drives uveitis. Highly expanded CD8 T cells expressed comparatively low levels of granzyme K, perforin and granulysin, suggesting these cells have reduced cytotoxic potential within the immune privileged eye. We found a wide variation between patients in the degree of clonal expansion, leading us to hypothesized that the quality of immune responses may vary between disease types. We therefore used principal component analysis to determine whether the aggregate composition of immune cells could differentiate clinical disease subtypes. We then performed bootstrapping to generate confidence intervals for each variable and identified 7 which contributed robustly to discriminating patients with distinct clinical presentations. These notably included the degree of clonal expansion of CD4 and CD8 T cells, as well as B cells, suggesting that antigen-driven inflammation is a key pathophysiologic feature differentiating patients with uveitis.