Rheumatoid Arthritis Synovial IL-21+CD4+ T Cells Specifically Induce Matrix Metalloproteinase Production By Fibroblast-Like Synoviocytes

Maria C. Lebre¹, Pedro L. Vieira², Saïda Aarrass¹, Thomas Newsom-Davis², Paul Peter Tak³ and Gavin R. Screaton², ¹Clinical Immunology and Rheumatology & Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, ²Department of Immunology, Imperial College London, London, United Kingdom, ³Academic Medical Center / University of Amsterdam, Department of Clinical Immunology and Rheumatology & GlaxoSmithKline, Amsterdam, Netherlands

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: interleukins (IL), matrix metalloproteinase (MMP) and rheumatoid arthritis (RA), Synovial Immune Biology, T cells

Session Information

Title: T-cell Biology in Autoimmune Diseases

Session Type: Abstract Submissions (ACR)

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) or IL-21-CD4+ T cells (p=0.0035 and p=0.0088, respectively). This induction was specific since 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 and might be a therapeutic target in RA.

Disclosure:

M. C. Lebre,
None;

P. L. Vieira,
None;

S. Aarrass,
None;

T. Newsom-Davis,
None;

P. P. Tak,
None;

G. R. Screaton,
None.

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