title: 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.
authors.affiliation: University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Pediatric Immunology and Immunology Advanced Center on Preclinical Immuno-genomics Institute for Translational Medicine, Utrecht, The Netherlands.
authors.forename: Ismé M
authors.initials: IM
authors.lastname: de Kleer
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Taams
authors.forename: Alka
authors.initials: A
authors.lastname: Patel
authors.forename: Hemlata
authors.initials: H
authors.lastname: Varsani
authors.forename: Mark
authors.initials: M
authors.lastname: Klein
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Gisela
authors.initials: G
authors.lastname: Pugayung
authors.forename: Francesca
authors.initials: F
authors.lastname: Giannoni
authors.forename: Ger
authors.initials: G
authors.lastname: Rijkers
authors.forename: Salvatore
authors.initials: S
authors.lastname: Albani
authors.forename: Wietse
authors.initials: W
authors.lastname: Kuis
authors.forename: Berent
authors.initials: B
authors.lastname: Prakken
mesh_terms: D000293:Adolescent; D000328:Adult; D001171:Arthritis, Juvenile / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000276:immunology* / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000097:blood; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D012075:Remission, Spontaneous; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma