CD4+CD25bright Regulatory T Cells Actively Regulate Inflammation in the Joints of Patients with the Remitting Form of Juvenile Idiopathic Arthritis

Abstract

This study investigates the role of CD4⁺CD25⁺ regulatory T cells during the clinical course of juvenile idiopathic arthritis (JIA). Persistent oligoarticular JIA (pers-OA JIA) is a subtype of JIA with a relatively benign, self-remitting course while extended oligoarticular JIA (ext-OA JIA) is a subtype with a much less favorable prognosis. Our data show that patients with pers-OA JIA display a significantly higher frequency of CD4⁺CD25^bright T cells with concomitant higher levels of mRNA FoxP3 in the peripheral blood than ext-OA JIA patients. Furthermore, while numbers of synovial fluid (SF) CD4⁺CD25^bright T cells were equal in both patient groups, pers-OA JIA patients displayed a higher frequency of CD4⁺CD25^int T cells and therefore of CD4⁺CD25^total in the SF than ext-OA JIA patients. Analysis of FoxP3 mRNA levels revealed a high expression in SF CD4⁺CD25^bright T cells of both patient groups and also significant expression of FoxP3 mRNA in the CD4⁺CD25^int T cell population. The CD4⁺CD25^bright cells of both patient groups and the CD4⁺CD25^int cells of pers-OA JIA patients were able to suppress responses of CD25^neg cells in vitro. A markedly higher expression of CTLA-4, glucocorticoid-induced TNFR, and HLA-DR on SF CD4⁺CD25^bright T regulatory (Treg) cells compared with their peripheral counterparts suggests that the CD4⁺CD25⁺ Treg cells may undergo maturation in the joint. In correlation with this mature phenotype, the SF CD4⁺CD25^bright T cells showed an increased regulatory capacity in vitro compared with peripheral blood CD4⁺CD25^bright T cells. These data suggest that CD4⁺CD25^bright Treg cells play a role in determining the patient’s fate toward either a favorable or unfavorable clinical course of disease.