Article Text


A8.9 Rheumatoid arthritis synovial IL-21 + CD4+ t cells specifically induce matrix metalloproteinase production by fibroblast-like synoviocytes
  1. M Cristina Lebre1,2,
  2. Pedro L Vieira3,
  3. Saida Aarrass1,2,
  4. Thomas Newsom-Davis3,
  5. Paul P Tak1,
  6. Gavin R Screaton3
  1. 1Amsterdam Rheumatology & Immunology Center
  2. 2Department Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  3. 3Department of Immunology, Imperial College London, Hammersmith Campus, London, UK


Background/Purpose IL-21 is a cytokine produced by activated CD4+ T cells and T follicular helper cells (TFh) that has been implicated in several autoimmune diseases including rheumatoid arthritis (RA). IL-21 regulates antibody production by B cells and induces osteoclastogenesis, mechanisms that contribute to rheumatoid arthritis (RA) pathology. Importantly, IL-21R blockade ameliorates arthritis in mice. Here we investigated the functional characteristics of synovial CD4+ IL-21 + T cells in RA.

Methods Matched peripheral blood (PB) and synovial fluid (SF) from 13 RA and 6 psoriatic arthritis (PsA) patients, and PB of 17 healthy control (HC) subjects were stimulated with PMA/Ionomycin/brefeldin A and intracellular cytokine production assessed by FACS. STAT3-dependent IL-21 production by SF CD4+ T cells was investigated by using a STAT3 specific inhibitor (WP1066). The effects of IL-21 were evaluated on cytokine and matrix metalloproteinase (MMP) release by RA synovial biopsies. In addition, the capacity of sorted RA SF IL-21 + or IL-21-CD4+ T cells in mediator release by fibroblast-like synoviocytes (FLS) was evaluated in co-cultures. IL-21, IL-6 and MMP-1 and MMP-3 concentrations were assessed by ELISA.

Results The frequency of both SF IL-21 + CD4+ or IL-21 + TNF-a + CD4+ T cells in RA was significantly higher compared to PsA (p = 0.0140 and p = 0.0038, respectively). STAT3-specific inhibitor blocked significantly the production of IL-21 by SF CD4+ T cells. Synovial IL-21 + CD4+ T cells did not phenotypically fit the TFh cell paradigm in that they did not co-express CXCR5 and ICOS. The levels of SF IL-21 were associated with CRP, MMP-1 and MMP-3. Related to this, IL-21 selectively induced MMP-1 and MMP-3 secretion by RA synovial biopsies. Sorted SF IL-21 + CD4+ T cells induced specifically the release of MMP-1 and MMP-3 by FLS compared to medium (both p < 0.0001) while IL-21-CD4+ T cells were not able to induce these MMPs. In addition, the capacity of IL-21 + and IL-21- CD4+ T cells to induce IL-6 production by FLS was similar.

Conclusion The results of this study support the notion that RA IL-21-producing CD4 T cells are involved in promoting joint destruction by inducing MMP release. Therefore IL-21 might be a therapeutic target in RA.

Statistics from

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.