Opposing Dynamics of CD4 + Regulatory and CD8 + Foxp3+ T Cells Characterize Immune Imbalance in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by persistent inflammation and joint damage from impaired immune tolerance. While CD4 + regulatory T cells (Tregs) are key to immune balance, their ability to restore tolerance in RA remains insufficient. Recently, CD8 + Foxp3+T have emerged as distinct regulators of immune tolerance, and investigating their role may provide new insights into the pathogenesis of RA. We enrolled 51 RA patients and 27 healthy controls. RA patients were grouped by disease activity: low-to-moderate (L-M RA) or high (H RA). We analyzed clinical data and lymphocyte subsets, including CD4 + Tregs and CD8 + Foxp3+T, to identify key immunological differences between RA and HC. Internal validation was performed using bootstrapping, and P-values were adjusted for false discovery rate (FDR) to ensure robustness. (1) CD4 + Tregs decreased in RA, especially in H RA, while CD8 + Foxp3+T increased, most in L-M RA. (2) CD4 + Tregs correlated negatively with IL-2, IL-4, and IL-10, whereas CD8 + Foxp3+T correlated negatively with ESR, DAS28, and RF-IgA/IgG. (3) The CD4 + Treg/CD8 + Foxp3+T ratio distinguished RA from controls. The combined model (including TNF-α and CD4 + Treg%) demonstrated strong discrimination with an AUC of 0.928 (optimism-corrected AUC: 0.912). CD8 + Foxp3+ T were increased in patients with RA and exhibited a trend opposite to that of CD4 + Treg. These two cell populations were associated with disease activity from distinct immunological perspectives. Furthermore, the CD4 + Treg/CD8 + Foxp3+T ratio and the combination of CD4 + Treg% with TNF-α showed potential value in distinguishing patients with RA from healthy controls. These findings provide additional insight into the immunological characteristics of RA and support further investigation into the biological significance of CD8 + Foxp3+ T cells.