Single-cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren’s syndrome

Primary Sjogren's syndrome (pSS) is a systemic autoimmune inflammatory disease mainly defined by T cell–dominated destruction of exocrine glands. Currently, CD8+T cells were closely related to the pathogenesis of pSS. However, the single-cell immune profiling of pSS and molecular signatures of pathogenic CD8+T cells have not been well elucidated. Our multiomics investigation identified that both T cell and B cell, especially CD8+T cells, were undergoing significant clonal expansion in pSS patients. TCR clonality analysis revealed that peripheral granzyme (GZM) K+CXCR6+CD8+T cells had higher proportion of shared clones with CD69+CD103-CD8+ tissue resident memory T (TRM) cells in labial glands in pSS. CD69+CD103-CD8+TRM cells featured by high expression of GZMK were more active and cytotoxic in pSS compared with their CD103+ counterparts. Peripheral GZMK+CXCR6+CD8+T cells with higher CD122 expression were increased and harbored a gene signature similar to TRM cells in pSS. Consistently, IL-15 was significantly elevated in pSS plasma and showed the capacity to promote differentiation of CD8+T cells into GZMK+CXCR6+CD8+T cells in a STAT5 dependent manner. Taken together, we depicted the immune landscape of pSS and further conducted comprehensive bioinformatics analysis and in vitro experimental investigation to characterize the pathogenic role and differentiation trajectory of CD8+TRM cells in pSS.