title: Acidification-dependent activation of CD1d-restricted natural killer T cells is intact in cystic fibrosis.
abstract: CD1d-restricted natural killer T (NKT) cells are emerging as critical regulators of the immune response to infectious agents, including Pseudomonas aeruginosa; and therapies to augment NKT-cell activation may represent a novel approach to treat chronic, antibiotic-resistant bacterial infections. We examined the capacity of dendritic cells (DCs) from people with cystic fibrosis (CF) to activate NKT cells. Our study was motivated by three lines of evidence: (i) NKT cells play a critical role in clearing P. aeruginosa infection; (ii) activation of NKT cells requires acidification-dependent processing of glycolipid antigens within the endolysosomal compartment; and (iii) endolysosomal acidification may be reduced in CF. We demonstrated that NKT-cell activation was dependent upon intact organelle acidification as inhibitors of the vacuolar (H(+))-ATPases prevented DCs from activating NKT cells with two glycolipid antigens, alpha-galactosylceramide and galactose-galactosylceramide. In contrast, cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel dysfunction had no significant biological impact on the capacity of DCs to activate NKT cells. Dendritic cells from subjects with CF and DCs treated with the thiazolidinone CFTR(inh)-172 inhibitor showed no reduction in their ability to activate NKT cells. Based on these data, we find no evidence for an inherent defect in glycolipid antigen presentation to NKT cells in CF subjects.
authors.affiliation: Department of Pediatrics, BC Children's Hospital and Child & Family Research Institute, University of British Columbia, Vancouver, BC.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Rzemieniak
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Hirschfeld
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Victor
authors.forename: Mark A
authors.initials: MA
authors.lastname: Chilvers
authors.forename: Dongjun
authors.initials: D
authors.lastname: Zheng
authors.forename: Peter
authors.initials: P
authors.lastname: van den Elzen
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000276:immunology; D011992:Endosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005699:Galactosylceramides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008297:Male; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000942:Antigens, Bacterial; D055610:Antigens, CD1d; C526877:CD1D protein, human; C505032:CFTR protein, human; D005699:Galactosylceramides; D045162:Thiazolidinediones; C493154:alpha-galactosylceramide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator