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

• Published in: The Journal of immunology (1950) 2004-05, Vol.172 (10), p.6435-6443
• Main Authors: de Kleer, Isme M, Wedderburn, Lucy R, Taams, Leonie S, Patel, Alka, Varsani, Hemlata, Klein, Mark, de Jager, Wilco, Pugayung, Gisela, Giannoni, Francesca, Rijkers, Ger, Albani, Salvatore, Kuis, Wietse, Prakken, Berent
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Arthritis, Juvenile - blood; Arthritis, Juvenile - immunology; Arthritis, Juvenile - pathology; Biomarkers - blood; Cartilage, Articular - immunology; Cartilage, Articular - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Differentiation - immunology; Child; Child, Preschool; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - blood; Female; Forkhead Transcription Factors; Humans; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-2 - pharmacology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - pathology; Lymphocyte Count; Male; Receptors, Interleukin-2 - biosynthesis; Receptors, Interleukin-2 - blood; Receptors, Interleukin-2 - metabolism; Remission, Spontaneous; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; Synovial Fluid - cytology; Synovial Fluid - immunology; Synovial Fluid - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.10.6435

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.