IL-10-Expressing Th2 Cells Contribute to the Elevated Antibody Production in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease associated with progressive disability, systemic complications, and early death. Multiple lines of evidence have placed adaptive immune responses in the center of RA pathogenesis. However, the functional roles of T helper cells are insufficiently described. Here, we examined the Th2 cell subsets and their functions in RA patients. A downregulation of IL-4⁺ cells in CD4⁺ T cells were observed in RA patients, indicating a downregulation of Th2 cells, and these results were confirmed by using and CXCR3 and CCR6 surface markers. We then found that CXCR3^-CCR6⁻ Th2 cells can be separated into IL-4⁺ (single positive), IL-10⁺ (single positive), and IL-4⁺IL-10⁺ (double positive) subsets. Further results showed that CXCR5 only expressed on IL-10+ Th2 cells. The CXCR5⁺ and CXCR5⁻ Th2 cells each exhibited distinctive features in helping B cell antibody secretion. CXCR5⁺ Th2 cells were more potent at stimulating total Ig and IgM secretion, while CXCR5⁻ Th2 cells were more potent at stimulating IgE. IL-10 was required for helping B cell total Ig, IgM, and IgE production, while IL-4 was required for total Ig and IgE. The frequencies of IL-10⁺ and IL-4⁺IL-10⁺ Th2 cells were positively correlated with rheumatoid factor titer in vivo. Together, our study demonstrated distinctive subsets within Th2 cells, each with different impacts on antibody production and RA disease.