title: Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers.
abstract: OBJECTIVE
  To identify interleukin-17 (IL-17)-producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL-17+ T cell numbers correlate with clinical phenotype in childhood arthritis.
  
  
  METHODS
  Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL-17-producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)-positive Treg cells. Migration of IL-17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL-17 and IL-22.
  
  
  RESULTS
  IL-17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL-17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL-17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL-17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL-17+ T cells had variable CCR4 expression. A proportion of IL-17+ synovial T cells produced IL-22 and interferon-gamma.
  
  
  CONCLUSIONS
  This study is the first to define the frequency and characteristics of "Th17" cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL-17+ T cells and Treg cells may be critical to outcome.
authors.affiliation: University College London, London, UK.
authors.forename: Kiran
authors.initials: K
authors.lastname: Nistala
authors.forename: Halima
authors.initials: H
authors.lastname: Moncrieffe
authors.forename: Katy R
authors.initials: KR
authors.lastname: Newton
authors.forename: Hemlata
authors.initials: H
authors.lastname: Varsani
authors.forename: Patricia
authors.initials: P
authors.lastname: Hunter
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
mesh_terms: D000293:Adolescent; D000328:Adult; D001171:Arthritis, Juvenile / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D054418:Chemokine CCL20 / Q000494:pharmacology; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007596:Joints / Q000378:metabolism* / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008297:Male; D010641:Phenotype; D054398:Receptors, CCR4 / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D054418:Chemokine CCL20; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D020381:Interleukin-17; D015847:Interleukin-4; D007378:Interleukins; D019402:Macrophage Inflammatory Proteins; D054398:Receptors, CCR4; D000097043:Interleukin-22; C108355:CCL20 protein, human; C515354:CCR4 protein, human; C418974:FOXP3 protein, human