EXTENDED REPORT

Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis

Frank Behrens¹, Andrea Himsel¹, Stefan Rehart², Joanna Stanczyk³, Björn Beutel¹, Stefanie Y Zimmermann⁴, Ulrike Koehl⁴, Burkhard Möller^2,5, Steffen Gay³, Joachim P Kaltwasser², Josef M Pfeilschifter¹, Heinfried H Radeke¹

¹ pharmazentrum frankfurt/ZAFES, J.W. Goethe University, Frankfurt/Main, Germany
² Centre for Rheumatic Diseases/ZAFES, J.W. Goethe University, Frankfurt/Main, Germany
³ WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University of Zurich, Switzerland
⁴ Clinic for Paediatric Oncology/ZAFES, J.W. Goethe University, Frankfurt/Main, Germany
⁵ Department for Rheumatology, Clinical Immunology and Allergology, Inselspital Berne, Switzerland

Correspondence to:
Prof Dr med Heinfried H Radeke
Dr-Hans-Schleussner Foundation of Immune Pharmacology, pharmazentrum frankfurt, ZAFES Clinic of the Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany; radeke{at}em.uni-frankfurt.de

Objectives: Regulatory T cells (Tregs) exert their anti-inflammatory activity predominantly by cell contact-dependent mechanisms. A study was undertaken to investigate the regulatory capacity of autologous peripheral blood Tregs in contact with synovial tissue cell cultures, and to evaluate their presence in peripheral blood, synovial tissue and synovial fluid of patients with rheumatoid arthritis (RA).

Methods: 44 patients with RA and 5 with osteoarthritis were included in the study. The frequency of interferon (IFN)-secreting cells was quantified in synovial tissue cell cultures, CD3-depleted synovial tissue cell cultures, synovial tissue cultures co-cultured with autologous CD4+ and with CD4+CD25+ peripheral blood T cells by ELISPOT. Total CD3+, Th1 polarised and Tregs were quantified by real-time PCR for CD3, T-bet and FoxP3 mRNA, and by immunohistochemistry for FoxP3 protein.

Results: RA synovial tissue cell cultures exhibited spontaneous expression of IFN which was abrogated by depletion of CD3+ T cells and specifically reduced by co-culture with autologous peripheral blood Treg. The presence of Treg in RA synovitis was indicated by FoxP3 mRNA expression and confirmed by immunohistochemistry. The amount of FoxP3 transcripts, however, was lower in the synovial membrane than in peripheral blood or synovial fluid. The T-bet/FoxP3 ratio correlated with both a higher grade of synovial tissue lymphocyte infiltration and higher disease activity.

Conclusion: This study has shown, for the first time in human RA, the efficacy of autologous Tregs in reducing the inflammatory activity of synovial tissue cell cultures ex vivo, while in the synovium FoxP3+ Tregs of patients with RA are reduced compared with peripheral blood and synovial fluid. This local imbalance of Th1 and Treg may be responsible for repeated rheumatic flares and thus will be of interest as a target for future treatments.

Abbreviations: IFN, interferon ; IL, interleukin; RA, rheumatoid arthritis; TNF, tumour necrosis factor; Treg, regulatory T cell

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