CD161⁺ Treg as a potential biomarker for evaluating disease activity and treatment efficacy in rheumatoid arthritis

CD161⁺ regulatory T cells (Tregs) are involved in rheumatoid arthritis (RA) pathogenesis. This study aimed to investigate the levels of circulating CD161⁺ Tregs in RA patients and to evaluate their associations with clinical features, laboratory indicators, and therapeutic responses.

A total of 172 RA patients meeting the 2010 ACR/EULAR criteria and 110 age- and sex-matched healthy controls (HCs) were enrolled. The proportion of CD161⁺ Tregs in peripheral blood was quantified by flow cytometry. Correlations between CD161⁺ Treg levels and clinical manifestations, laboratory parameters, and disease activity scores (DAS28) were assessed. Twenty-four RA patients were longitudinally followed to assess post-treatment changes in CD161⁺ Tregs and disease activity.

The proportions of CD161⁺ Tregs of the total Treg and CD4⁺ T cell populations were significantly elevated in RA patients compared to HCs (P < 0.001). Higher CD161⁺ Treg levels were associated with smoking history (P = 0.033) and inversely correlated with the presence of dry eye sicca (P = 0.030). These subsets showed positive correlations with IgA, IgM, rheumatoid factor (RF), RF-IgG, TNF-α⁺CD4⁺ T cell, Th17 and DAS28-ESR (P < 0.05), while exhibiting negative correlations with naïve Th cells and effector T (Teff) cells (P < 0.05). CD161⁺ Treg levels were higher in patients with long-standing RA (LRA) than in HCs (P < 0.05), and in patients with high disease activity (DAS28-ESR > 5.1) compared to those with moderate/low disease activity (P < 0.05). After treatment, decreased CD161⁺ Treg and disease activity scores were observed (P < 0.05), which were particularly pronounced in the group receiving csDMARDs combined with tocilizumab (an IL-6 inhibitor). However, csDMARDs alone or in combination with JAK inhibitors showed no or only partial efficacy.

CD161⁺ Tregs are elevated in RA and associated with disease activity and immunologic indicators. CD161⁺ Tregs might serve as a biomarker for assessing RA disease activity. Key Points • The proportion of circulating CD161⁺ regulatory T cells is significantly increased in rheumatoid arthritis patients compared to healthy controls. • Higher CD161⁺ Treg levels correlate positively with disease activity scores (DAS28-ESR) and key serological markers (RF, IgA, IgM). • CD161⁺ Treg levels decreased significantly following effective therapy, paralleling reductions in disease activity, particularly in the group receiving csDMARDs combined with tocilizumab. • CD161⁺ Tregs show positive correlations with pro-inflammatory cells (TNF-α+CD4+T cell, Th17) and peripheral T follicular helper cells, underscoring their role in RA immunopathology.