Abstract

Abstract Aim Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by immune dysegulation, including an immune imbalance due to abnormal activation of non‐classical Th1 cells (CD161 + Th1). This study investigated the effects of CCR5 on the activation and proliferation of CD161 + Th1 and their pathogenicity in patients with RA. Methods The study was conducted on 53 patients with RA and 32 age‐ and sex‐matched healthy controls (HC). The cell phenotype was assessed by flow cytometry and the cytokine levels in the supernatant were detected by ELISA. Results We demonstrate a marked increase in CD161 + Th1 cells in the synovial fluid of RA patients. These cells exhibit a hyperactivated and hyperproliferative state alongside elevated CCR5 expression. Furthermore, the levels of CD161 + Th1 cells, CD25, and CCR5 in RA synovial fluid show a positive correlation with the disease activity. Additionally, our study reveals that CCR5 facilitates the activation, proliferation, and cytokine production of CD161 + Th1 cells through the pZAP70/NFAT signaling pathway. Conclusion These findings contribute to a deeper understanding of RA pathogenesis and uncover a novel mechanism that regulates non‐classical CD161 + Th1 responses in RA, which may provide a potential therapeutic target.