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

J Leukoc Biol. 2017 Mar;101(3):775-783. doi: 10.1189/jlb.5A0516-217RR. Epub 2016 Oct 12.


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.

Keywords: autoimmune; inflammation; peripheral blood; synovial fluid.

MeSH terms

  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Biopsy
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Fibroblasts / pathology
  • Humans
  • Immunoglobulin M / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-6 / metabolism
  • Interleukins / metabolism*
  • Joints / pathology*
  • Matrix Metalloproteinase 1 / metabolism*
  • Matrix Metalloproteinase 3 / metabolism*
  • Peptides, Cyclic / metabolism
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • Psoriasis / immunology
  • Psoriasis / pathology
  • RANK Ligand / metabolism
  • Rheumatoid Factor / metabolism
  • Synovial Fluid / metabolism
  • Synoviocytes / metabolism*
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology
  • Tumor Necrosis Factor-alpha / metabolism*


  • BCL6 protein, human
  • Immunoglobulin M
  • Interleukin-17
  • Interleukin-6
  • Interleukins
  • Peptides, Cyclic
  • Proto-Oncogene Proteins c-bcl-6
  • RANK Ligand
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Tumor Necrosis Factor-alpha
  • cyclic citrullinated peptide
  • Interferon-gamma
  • Rheumatoid Factor
  • MMP3 protein, human
  • Matrix Metalloproteinase 3
  • MMP1 protein, human
  • Matrix Metalloproteinase 1
  • interleukin-21
  • interleukin-22