CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid.

OBJECTIVE: In mice, CD4(+)CD25(+) regulatory T cells play a pivotal role in preventing autoimmunity. Regulatory T cells are also present and functional in healthy humans. We investigated the presence, phenotype, and function of CD4(+)CD25(+) regulatory T cells in peripheral blood (PB) and synovial fluid (SF) from patients with rheumatoid arthritis (RA). METHODS: The presence and phenotype of CD4(+)CD25(+) regulatory T cells were determined by flow cytometry. Anergy and suppressive activity were assessed by culturing CD4(+)CD25(-) and CD4(+)CD25(+) T cells with anti-CD3 monoclonal antibodies and antigen-presenting cells, followed by proliferation and cytokine detection. RESULTS: The percentage of CD4(+)CD25(+) T cells in RA SF was significantly increased compared with that in RA PB, and both of these percentages were higher than that in PB from controls. The cells in RA PB were similar in phenotype and function to CD4(+)CD25(+) regulatory T cells from controls. In SF, however, approximately 40-50% of CD4(+)CD25(+) T cells expressed an activated phenotype, i.e., CD69+, class II MHC(+), OX-40(+), with high levels of CTLA-4 and glucocorticoid-induced tumor necrosis factor receptor. These synovial CD4(+)CD25(+) T cells displayed an increased suppressive capacity compared with blood CD4(+)CD25(+) T cells. However, this enhanced suppressive activity was counterbalanced, because activated responder T cells from SF were less susceptible to CD4(+)CD25(+) T cell-mediated suppression than were responder cells from PB. CONCLUSION: We demonstrate that CD4(+)CD25(+) regulatory T cells are present and functional in patients with RA, with higher numbers of regulatory T cells with increased suppressive activity found in SF compared with PB. These findings suggest a negative feedback system that is active at the site of inflammation. The balance between activated responder and regulatory T cells appears to influence the extent of immunoregulation in RA.