Pathologically expanded peripheral CD4⁺PD-1⁺Foxp3^- T-cell subset promotes B-cell hyperactivity in patients with rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive polyarthritis, and abnormal T-B-cell interactions may contribute to its pathogenesis. This study aimed to investigate the characteristics and roles of CD4(+) programmed death 1 (PD-1)(+)Foxp3(-) T cells in relation to the B-cell response in patients with RA. Methods: This study included 155 patients with RA and 36 age- and sex-matched healthy controls (HCs) from the Second Hospital of Dalian Medical University in China. Flow cytometry was used to assess the proportion and properties of peripheral CD4(+)PD-1(+)Foxp3(+) T cells, including their proliferation, activation, cytokine production, and capacity to induce B-cell differentiation. Results: The proportion of CD4(+)PD-1(+)Foxp3(-) T cells was increased in patients with RA compared with HCs ([10.78 +/- 0.60]% vs. [5.67 +/- 0.40]%, p < 0.001), and this was positively associated with the B-cell response. Compared with CD4(+)PD-1(+)Foxp3(+) T cells, CD4(+)PD-1(+)Foxp3(-) T cells from patients with RA exhibited increased expression of Ki67 ([6.52 +/- 0.41]% vs. [3.87 +/- 0.42]%, p < 0.01) and activation markers, produced higher levels of cytokines, and showed enhanced B-cell differentiation. Furthermore, anti-interleukin-6R antagonists decreased the proportion, activation, and cytokine production of CD4(+)PD-1(+)Foxp3(-) T cells in vitro. The frequency of type 2 CD4(+)PD-1(+)Foxp3(-) T cells was significantly higher in patients with RA than that in HCs ([37.27 +/- 1.43]% vs. [29.05 +/- 1.30]%, p < 0.05). Conclusions: Peripherally expanded CD4(+)PD-1(+)Foxp3(-) T cells in patients with RA, which induced B-cell hyperactivity, may be inclined toward type 2 helper T cells. Our findings revealed a novel T-cell subset that contributes to B-cell hyperactivity in the pathogenesis of RA.