Drs. van Amelsfort and van Roon contributed equally to this work.
Proinflammatory mediator–induced reversal of CD4+,CD25+ regulatory T cell–mediated suppression in rheumatoid arthritis
Article first published online: 27 FEB 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 3, pages 732–742, March 2007
How to Cite
van Amelsfort, J. M. R., van Roon, J. A. G., Noordegraaf, M., Jacobs, K. M. G., Bijlsma, J. W. J., Lafeber, F. P. J. G. and Taams, L. S. (2007), Proinflammatory mediator–induced reversal of CD4+,CD25+ regulatory T cell–mediated suppression in rheumatoid arthritis. Arthritis & Rheumatism, 56: 732–742. doi: 10.1002/art.22414
- Issue published online: 27 FEB 2007
- Article first published online: 27 FEB 2007
- Manuscript Accepted: 20 NOV 2006
- Manuscript Received: 17 FEB 2006
- Dutch Arthritis Association
We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg–mediated suppression.
Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25– and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNFα), or IL-7.
Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25– and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg–mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNFα, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg–mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression.
Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA.