Single‐cell analysis reveals CXCL16 + dendritic cells and clonally expanded GZMK + CD4 T cells driving joint inflammation in psoriatic arthritis

Objective Psoriatic arthritis (PsA) is a chronic immune‐mediated arthritis affecting approximately 30% of individuals with psoriasis. The mechanisms driving PsA joint inflammation remain incompletely defined. Methods To address this gap, we performed multimodal single‐cell sequencing of immune cells from matched peripheral blood and synovial fluid (SF) from 6 PsA patients, with comparisons to a rheumatoid arthritis (RA) patient and 6 healthy controls (HC). Results SF CD4 and CD8 T cells displayed elevated expression of TOX , PDCD1 , CTLA4 , GZMK , CXCR3 , and CXCR6 , reflecting a tissue‐specific activation state. CD4 T cell sub‐clustering revealed clonally expanded populations enriched for GZMK and cytotoxic gene programs, suggesting antigen‐driven activation. In contrast, CD8 T cell clonality showed a significant correlation with GZMK expression, however GZMK + CD8 T cells in the joint exhibited a transcriptional signature consistent with functional exhaustion. Concurrently, SF was enriched for CD141 + , CD1c + , CCR7 + , and SIGLEC6 + dendritic cells (DCs), characterized by increased CXCL16 expression and antigen presentation pathways. Flow cytometry and ELISA in an additional 25 PsA patients and 16 HCs confirmed protein‐level enrichment of key chemokines and GZMK + T cells. Cell–cell communication analysis highlighted CXCR6–CXCL16 and CXCR3–CXCL10 chemokine axes as mediators of immune cell recruitment and retention, while in vitro assays showed enhanced migration of PsA SF T cells toward a CXCL16 gradient relative to paired blood. Conclusion Together, these findings suggest that clonally expanded GZMK + CD4 T cells in PsA are cytotoxic and antigen‐responsive, contributing to joint inflammation following recruitment by CXCL16 ‐producing dendritic cells. image