The Journal of Experimental Medicine
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Published online 26 July 2004 doi:10.1084/jem.20040165
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 3, 277-285
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*Joint Disorders
*Rheumatoid Arthritis
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Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNF{alpha} Therapy

Michael R. Ehrenstein1, Jamie G. Evans1, Animesh Singh1, Samantha Moore1, Gary Warnes2, David A. Isenberg1, and Claudia Mauri1

1 Department of Medicine, Centre For Rheumatology, Windeyer Institute, University College London, London W1T 4JF, England, UK
2 Cancer Research UK, London WC2A 3PX, England, UK

Address correspondence to Michael R. Ehrenstein, Dept. of Medicine, Centre For Rheumatology, Windeyer Institute, University College London, London W1T 4JF, England, UK. Phone: 44-20-7380-9281; Fax: 44-20-7380-9278; email: m.ehrenstein{at}ucl.ac.uk; or Claudia Mauri, Phone: 44-20-7679-9670; Fax: 44-20-7679-9143; email: c.mauri{at}ucl.ac.uk

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25– T cells. Treatment with antitumor necrosis factor {alpha} (TNF{alpha}; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to "conventional" T cells. Furthermore, anti-TNF{alpha} treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNF{alpha} therapy may be a further mechanism by which this disease is ameliorated.

Key Words: T lymphocytes • tolerane • autoimmune disease • TNF{alpha} • cytokines

Abbreviations used in this paper: CBA, cytometric bead array; PB, peripheral blood; RA, rheumatoid arthritis.


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