GZMK⁺CD8⁺ T Cells Induce Acinar Cell Senescence and Salivary Secretion Impairment in Sjögren's Syndrome via Mitochondrial Dysfunction and TMEM16A Chloride Channel Disruption.

Immune cell-mediated damage to acinar cells plays a central role in Sjögren's syndrome (SS) pathogenesis, with T-cell recruitment being critical in the early stages. In this study, single-cell RNA sequencing was employed to generate transcriptomic profiles of labial gland tissues from SS patients, focusing on GZMK⁺CD8⁺ T cells and their correlation with SS clinical pathology. The role of GZMK⁺CD8⁺ T cells in inducing acinar cell senescence and secretory dysfunction was investigated by co-culturing SMG-C6 acinar cells with GZMK⁺CD8⁺ T cells and recombinant granzyme K. Mechanistically, GZMK induces oxidative stress and mitochondrial dysfunction, thereby promoting senescent phenotypes in acinar cells. Additionally, GZMK-mediated downregulation of TMEM16A contributes to reduced chloride transport and salivary secretion dysfunction. This study provides novel insights into the immune-epithelial crosstalk in SS progression by revealing the relationship between GZMK⁺CD8⁺ T cells and acinar cells. This pathogenic immune-epithelial interaction may offer a promising therapeutic strategy to mitigate SS progression in the early stages and restore salivary secretion in SS patients.