Synovial IL‐21/TNF‐producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast‐like synoviocytes

Synovial IL‐21+TNF+CD4+ T cells induce matrix metalloproteinase production by fibroblast‐like synoviocytes in RA patients. Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL‐21–producing cells T cells has been neglected. We sought to investigate the role of IL‐21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4+IL‐21+ T cells. We show that the frequency of both synovial fluid (SF) CD4+IL‐21+ or CD4+IL‐21+TNF+ T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL‐21+CD4+ T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti‐CCP) antibodies and IgM‐rheumatoid factor (IgM‐RF). IL‐21 levels in RA SF were associated with matrix metalloproteinase (MMP)‐1 and MMP‐3. Related to this, IL‐21 induced significantly the secretion of MMP‐1 and MMP‐3 in RA synovial biopsies. Sorted SF CD4+IL‐21+ T cells significantly induced the release of MMP‐1 and MMP‐3 by fibroblast‐like synoviocytes (FLS) compared with medium or CD4+IL‐21− T cells in a coculture system. Neutralization of both IL‐21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4+IL‐21+TNF+ T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL‐21 blockade in combination with anti‐TNF might be an effective therapy in patients with RA by inhibiting MMP‐induced inflammation/joint destruction.