Altered Peripheral and Synovial CD8⁺ T Cell Signatures Are Associated With Disease Activity in Female Early-Stage...

Rheumatoid arthritis (RA) exhibits significant sexual dimorphism, with females being two to three times more susceptible than males. CD8⁺ T cells are key effector immune cells driving synovial inflammation, bone erosion, and autoimmune injury within RA joints; nevertheless, their sex-specific pathogenic characteristics in early-stage RA (ERA) remain poorly defined. This study aimed to identify gender-specific pathogenic factors in RA. Based on a well-characterized patient cohort containing 46 RA individuals, we combined peripheral flow cytometry and synovial transcriptomic profiling to systematically compare immune infiltration and molecular alterations between male and female patients. Bioinformatic analyses were performed to screen differentially expressed genes and immune-related pathways, and synovial immunohistochemical (IHC) staining was applied for histological validation. The gene scores and infiltration levels of CD8⁺ T cells in the synovial tissue of female ERA patients were significantly elevated, a phenotype not observed in male ERA patients. Chemokines CCL3 and CCL4 were exclusively associated with synovial CD8⁺ T cell infiltration levels in female ERA, but not in males. The synovial CD8⁺ T cells were enriched in immune activation pathways. IHC staining confirmed infiltration of CD8⁺ T cells and the presence of CCL3 and CCL4 in the synovium of female ERA patients, supporting the concept that increased recruitment of CD8⁺ T cells to the synovium is a characteristic feature of female ERA. Importantly, CD8⁺ T-cell infiltration, associated with increased CCL3/CCL4 expression, correlated with disease activity and may therefore contribute to the pathogenesis of ERA in women. Collectively, these observations offer novel clues for gender-tailored diagnostic biomarkers and targeted therapies for female ERA.