title: Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome Immunopathology.
abstract: Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4+effector memory T (TEM) cells that secrete IL-17A, but not IFN-γ, was responsible for early IL-17A production. We found mouse "TEM-17" cells to be enriched within the intestinal epithelium and among lamina propria lymphocytes. Furthermore, interfering with IL-17A receptor signaling in human PBMCs attenuated the expression of numerous inflammatory mediators implicated in the TSS-associated cytokine storm. IL-17A receptor blockade also abrogated the secondary effect of SAg-stimulated PBMCs on human dermal fibroblasts as judged by C/EBP δ expression. Finally, the early IL-17A response to SAgs was pathogenic because in vivo neutralization of IL-17A in humanized mice ameliorated hepatic and intestinal damage and reduced mortality. Together, our findings identify CD4+TEMcells as a key effector of TSS and reveal a novel role for IL-17A in TSS immunopathogenesis. Our work thus elucidates a pathogenic, as opposed to protective, role for IL-17A during Gram-positive bacterial infections. Accordingly, the IL-17-IL-17R axis may provide an attractive target for the management of SAg-mediated illnesses.
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Szabo
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada.
authors.forename: Ankur
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada.
authors.forename: Delfina M
authors.initials: DM
authors.lastname: Mazzuca
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada.
authors.forename: Kyoungok
authors.initials: K
authors.lastname: Kim
authors.affiliation: Cell and Molecular Biology Laboratory, Roth | McFarlane Hand and Upper Limb Centre, Western University, London, Ontario N6A 4V2, Canada.|Department of Biochemistry, Western University, London, Ontario N6A 5C1, Canada.|Lawson Health Research Institute, London, Ontario N6C 2R5, Canada.|Department of Surgery, Western University, London, Ontario N6A 4V2, Canada.
authors.forename: David B
authors.identifier: 0000-0001-6195-2644
authors.initials: DB
authors.lastname: O'Gorman
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario N6A 5C1, Canada.|Krembil Centre for Stem Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, London, Ontario N6A 5B7, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Hess
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Welch
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702.
authors.forename: Howard A
authors.identifier: 0000-0002-3118-5111
authors.initials: HA
authors.lastname: Young
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada.|Lawson Health Research Institute, London, Ontario N6C 2R5, Canada.|Centre for Human Immunology, Western University, London, Ontario N6A 5C1, Canada; and.
authors.forename: Bhagirath
authors.identifier: 0000-0002-9792-8694
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada.|Lawson Health Research Institute, London, Ontario N6C 2R5, Canada.|Centre for Human Immunology, Western University, London, Ontario N6A 5C1, Canada; and.
authors.forename: John K
authors.identifier: 0000-0003-3742-7289
authors.initials: JK
authors.lastname: McCormick
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario N6A 5C1, Canada; Mansour.Haeryfar@schulich.uwo.ca.|Lawson Health Research Institute, London, Ontario N6C 2R5, Canada.|Centre for Human Immunology, Western University, London, Ontario N6A 5C1, Canada; and.|Division of Clinical Immunology and Allergy, Department of Medicine, Western University, London, Ontario N6A 5A5, Canada.
authors.forename: S M Mansour
authors.identifier: 0000-0002-1125-8176
authors.initials: SM
authors.lastname: Haeryfar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016908:Gram-Positive Bacterial Infections / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17