Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy.
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 (TNFalpha; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to "conventional" T cells. Furthermore, anti-TNFalpha 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-TNFalpha therapy may be a further mechanism by which this disease is ameliorated.
Dept. of Medicine, Centre For Rheumatology, Windeyer Institute, University College London, London W1T 4JF, England, UK. m.ehrenstein@ucl.ac.uk
Michael R
MR
Ehrenstein
Jamie G
JG
Evans
Animesh
A
Singh
Samantha
S
Moore
Gary
G
Warnes
David A
DA
Isenberg
Claudia
C
Mauri
D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy; D015704:CD4 Antigens / Q000032:analysis*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D015704:CD4 Antigens; D016207:Cytokines; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10