title: Superantigenic Yersinia pseudotuberculosis induces the expression of granzymes and perforin by CD4+ T cells.
abstract: Bacterial superantigens (SAgs) are immunostimulatory toxins that induce acute diseases mainly through the massive release of inflammatory cytokines. Yersinia pseudotuberculosis is the only Gram-negative bacterium known to produce a SAg (Y. pseudotuberculosis-derived mitogen [YPM]). This SAg binds major histocompatibility complex class II molecules on antigen-presenting cells and T cell receptors (TcR) bearing the variable region Vβ3, Vβ9, Vβ13.1, or Vβ13.2 (in humans) and Vβ7 or Vβ8 (in mice). We have previously shown that YPM exacerbates the virulence of Y. pseudotuberculosis in mice. With a view to understanding the mechanism of YPM's toxicity, we compared the immune response in BALB/c mice infected with a YPM-producing Y. pseudotuberculosis or the corresponding isogenic, SAg-deficient mutant. Five days after infection, we observed strong CD4(+) Vβ7(+) T cell expansion and marked interleukin-4 (IL-4) production in mice inoculated with SAg-producing Y. pseudotuberculosis. These phenomena were correlated with the activation of ypm gene transcription in liver and spleen. A transcriptomic analysis revealed that the presence of YPM also increased expression of granzyme and perforin genes in the host's liver and spleen. This expression was attributed to a CD4(+) T cell subset, rather than to natural killer T (NKT) cells that display a TcR with a Vβ region that is potentially recognized by YPM. Increased production of cytotoxic molecules was correlated with hepatotoxicity, as demonstrated by an increase in plasma alanine aminotransferase activity. Our results demonstrate that YPM activates a potentially hepatotoxic CD4(+) T cell population.
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Goubard
authors.affiliation: Laboratoire de Bactériologie Hygiène, Institut de Microbiologie, Centre de Biologie Pathologie, CHRU Lille, Lille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Loïez
authors.affiliation: National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fichel
authors.affiliation: Laboratoire de Bactériologie Hygiène, Institut de Microbiologie, Centre de Biologie Pathologie, CHRU Lille, Lille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Herwegh
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Faveeuw
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Porte
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Cayet
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Sebbane
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Pathologie, CHRU Lille, Lille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Penet
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Foligné
authors.affiliation: INSERM U995, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.affiliation: National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Sirard
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France Laboratoire de Bactériologie Hygiène, Institut de Microbiologie, Centre de Biologie Pathologie, CHRU Lille, Lille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Simonet
authors.affiliation: Université Lille Nord de France, INSERM U1019, CNRS UMR 8204, and Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France christophe.carnoy@univ-lille2.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Carnoy
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D020869:Gene Expression Profiling; D053804:Granzymes / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008807:Mice, Inbred BALB C; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000382:microbiology; D015011:Yersinia pseudotuberculosis / Q000276:immunology*
chemical_list: D052899:Pore Forming Cytotoxic Proteins; D018089:Superantigens; C483886:perforin, mouse; D053804:Granzymes