title: Intrinsic predisposition of naïve cystic fibrosis T cells to differentiate towards a Th17 phenotype.
abstract: BACKGROUND
  Cystic fibrosis (CF) is a complex, multi-system, life-shortening, autosomal recessive disease most common among Caucasians. Pulmonary pathology, the major cause of morbidity and mortality in CF, is characterized by dysregulation of cytokines and a vicious cycle of infection and inflammation. This cycle causes a progressive decline in lung function, eventually resulting in respiratory failure and death. The Th17 immune response plays an active role in the pathogenesis of CF pulmonary pathology, but it is not known whether the pathophysiology of CF disease contributes to a heightened Th17 response or whether CF naïve CD4+ T lymphocytes (Th0 cells) intrinsically have a heightened predisposition to Th17 differentiation.
  
  
  METHODS
  To address this question, Th0 cells were isolated from the peripheral blood of CF mice, human CF subjects and corresponding controls. Murine Th0 cells were isolated from single spleen cell suspensions using fluorescence-activated cell sorting. Lymphocytes from human buffy coats were isolated by gradient centrifugation and Th0 cells were further isolated using a human naïve T cell isolation kit. Th0 cells were then assessed for their capacity to differentiate along Th17, Th1 or Treg lineages in response to corresponding cytokine stimulation. The T cell responses of human peripheral blood cells were also assessed ex vivo using flow cytometry.
  
  
  RESULTS
  Here we identify in both mouse and human CF an intrinsically enhanced predisposition of Th0 cells to differentiate towards a Th17 phenotype, while having a normal propensity for differentiation into Th1 and Treg lineages. Furthermore, we identify an active Th17 response in the peripheral blood of human CF subjects.
  
  
  CONCLUSIONS
  We propose that these novel observations offer an explanation, at least in part, for the known increased Th17-associated inflammation of CF and the early signs of inflammation in CF lungs before any evidence of infection. Moreover, these findings point towards direct modulation of T cell responses as a novel potential therapeutic strategy for combating excessive inflammation in CF.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kushwah
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gagnon
authors.affiliation: Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. neil.sweezey@sickkids.ca.
authors.forename: Neil B
authors.initials: NB
authors.lastname: Sweezey
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator