IL-21 regulates Th17 cells in rheumatoid arthritis

IL-21 is a type I cytokine that like IL-2, IL-4, IL-7, IL-9, and IL-15 uses the common gamma chain of cytokine receptor. IL-21 has been shown to regulate the function of T cells, B cells, natural killer cells, and dendritic cells in immune responses. Although activated CD4(+) T cells produce IL-21, recent data suggest that novel subsets of effector T cells are the major producers in immune responses. In this study, we show that IL-21 expression correlates with the presence of Th17 cells in synovial fluid (SF) and peripheral blood in rheumatoid arthritis patients. Human CCR6+ CD4(+) T cells produce high levels of both IL-21 and IL-17. Similar to mouse T cells, IL-21 auto-regulates its own production in human CD4(+) T cells. IL-21 potently enhances Th17 proliferation and suppresses Foxp3 expression, leading to the expression of RORC. IL-21 is therefore an autocrine cytokine that regulates human Th17 cells in rheumatoid arthritis, and serves as a good target for treating this autoimmune disease.