Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti–tumor necrosis factor antibody therapy
Article first published online: 27 SEP 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 10, pages 3129–3138, October 2012
How to Cite
McGovern, J. L., Nguyen, D. X., Notley, C. A., Mauri, C., Isenberg, D. A. and Ehrenstein, M. R. (2012), Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti–tumor necrosis factor antibody therapy. Arthritis & Rheumatism, 64: 3129–3138. doi: 10.1002/art.34565
- Issue published online: 27 SEP 2012
- Article first published online: 27 SEP 2012
- Accepted manuscript online: 5 JUN 2012 10:39AM EST
- Manuscript Accepted: 24 MAY 2012
- Manuscript Received: 19 DEC 2011
- Arthritis Research UK
- University College London Hospital Comprehensive Biomedical Research Centre
- Bloomsbury Rheumatology Discretionary Fund
The importance of interleukin-17 (IL-17) is underscored both by its resistance to control by Treg cells and the propensity of Treg cells to produce this highly inflammatory cytokine. This study sought to address whether Th17 cells are inhibited by Treg cells in rheumatoid arthritis (RA) patients responding to anti–tumor necrosis factor (anti-TNF) therapy, and if so defining the underlying mechanisms of suppression.
Inhibition of Th17 cell responses was determined by Treg cell suppression assays. The Treg cell phenotype was analyzed using flow cytometry and enzyme-linked immunosorbent assay. Mechanisms of suppression were tested by cytokine addition or antibody blockade.
Th17 responses were inhibited by Treg cells from RA patients responding to the anti-TNF antibody adalimumab (Tregada), but not by Treg cells from healthy individuals or patients with active RA. Furthermore, Tregada cells secreted less IL-17, even when exposed to proinflammatory monocytes from patients with active RA. Tregada cells suppressed Th17 cells through the inhibition of monocyte-derived IL-6, but this effect was independent of IL-10 and transforming growth factor β, which mediated the suppression of Th1 responses. Adalimumab therapy led to a reduction in retinoic acid receptor–related orphan nuclear receptor C–positive Th17 cells and an increase in FoxP3+ Treg cells lacking expression of the transcription factor Helios. However, this acquisition of IL-17–suppressor function was not observed in RA patients responding to treatment with etanercept, a modified TNF receptor–Fc fusion protein. Indeed, there was no alteration in Treg cell number, function, or phenotype in etanercept-treated patients, and Th17 responses remained unchecked.
Th1 and Th17 responses are controlled through distinct mechanisms by Treg cells from patients responding to anti-TNF antibody therapy. Adalimumab therapy, but not etanercept therapy, induces a potent and stable Treg cell population with the potential to restrain the progression of IL-17–associated inflammation in RA via regulation of monocyte-derived IL-6.