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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

Abstract

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.

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