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Open Access Highly Accessed Research article

Resting CD4+ effector memory T cells are precursors of bystander-activated effectors: a surrogate model of rheumatoid arthritis synovial T-cell function

Fionula M Brennan1*, Nicola MG Smith1, Sally Owen1, Ching Li1, Parisa Amjadi1, Patricia Green1, Anna Andersson1, Andrew C Palfreeman1, Philippa Hillyer1, Andrew Foey2, Jonathan T Beech1 and Marc Feldmann1

Author Affiliations

1 Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, Aspenlea Road, London, W6 8LH, UK

2 School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth, PL4 8AA, UK

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Arthritis Research & Therapy 2008, 10:R36  doi:10.1186/ar2390

Published: 19 March 2008

Abstract

Background

Previously we described a system whereby human peripheral blood T cells stimulated for 8 days in a cytokine cocktail acquired effector function for contact-dependent induction of proinflammatory cytokines from monocytes. We termed these cells cytokine-activated (Tck) cells and found that the signalling pathways elicited in the responding monocytes were identical whether they were placed in contact with Tck cells or with T cells isolated from rheumatoid arthritis (RA) synovial tissue.

Methods

Here, using magnetic beads and fluorescence-activated cell sorting, we extensively phenotype the Tck effector cells and conclude that effector function resides within the CD4+CD45RO+, CCR7-, CD49dhigh population, and that these cells are derived from the effector memory CD4+ T cells in resting blood.

Results

After stimulation in culture, these cells produce a wide range of T-cell cytokines, undergo proliferation and differentiate to acquire an extensively activated phenotype resembling RA synovial T cells. Blocking antibodies against CD69, CD18, or CD49d resulted in a reduction of tumour necrosis factor-α production from monocytes stimulated with CD4+CD45RO+ Tck cells in the co-culture assay. Moreover, blockade of these ligands also resulted in inhibition of spontaneous tumour necrosis factor-α production in RA synovial mononuclear cell cultures.

Conclusion

Taken together, these data strengthen our understanding of T-cell effector function, highlight the multiple involvement of different cell surface ligands in cell-cell contact and, provide novel insights into the pathogenesis of inflammatory RA disease.