title: Invariant Natural Killer T Cells Are Pathogenic in the HLA-DR4-Transgenic Humanized Mouse Model of Toxic Shock Syndrome and Can Be Targeted to Reduce Morbidity.
abstract: During toxic shock syndrome (TSS), bacterial superantigens trigger a polyclonal T -cell response leading to a potentially catastrophic "cytokine storm". Whether innate-like invariant natural killer T (iNKT) cells, with remarkable immunomodulatory properties, participate in TSS is unclear. Using genetic and cell depletion approaches, we generated iNKT cell-deficient, superantigen-sensitive HLA-DR4-transgenic (DR4tg) mice, which were compared with their iNKT-sufficient counterparts for responsiveness to staphylococcal enterotoxin B (SEB). Both approaches indicate that iNKT cells are pathogenic in TSS. Importantly, treating DR4tg mice with a TH2-polarizing glycolipid agonist of iNKT cells reduced SEB-inflicted morbidity/mortality. Therefore, iNKT cells may constitute an attractive therapeutic target in superantigen-mediated illnesses.
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Szabo
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Rudak
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Stacey X
authors.initials: SX
authors.lastname: Xu
authors.affiliation: NKT Therapeutics, Inc, Waltham, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schaub
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.|Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.|Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: John K
authors.initials: JK
authors.lastname: McCormick
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.|Lawson Health Research Institute, London, Ontario, Canada.|Department of Medicine, Division of Clinical Immunology and Allergy, Western University, London, Ontario, Canada.
authors.forename: S M Mansour
authors.initials: SMM
authors.lastname: Haeryfar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology*; D012772:Shock, Septic / Q000276:immunology* / Q000517:prevention & control*; D018089:Superantigens / Q000097:blood / Q000276:immunology
chemical_list: D004768:Enterotoxins; D015804:HLA-DR4 Antigen; D018089:Superantigens; C031818:enterotoxin B, staphylococcal
keywords: Invariant natural killer T cells; Staphylococcus aureus; inflammation; staphylococcal enterotoxin B; superantigen; toxic shock syndrome; cytokines