Goubard Agathe, Loïez Caroline, Abe Jun, Fichel Caroline, Herwegh Stéphanie, Faveeuw Christelle, Porte Rémi, Cayet Delphine, Sebbane Florent, Penet Sylvie, Foligné Benoit, Desreumaux Pierre, Saito Hirohisa, Sirard Jean-Claude, Simonet Michel, Carnoy Christophe
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.
Infect Immun. 2015 May;83(5):2053-64. doi: 10.1128/IAI.02339-14. Epub 2015 Mar 9.
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.
细菌超抗原（SAgs）是免疫刺激毒素，主要通过大量释放炎性细胞因子诱导急性疾病。假结核耶尔森菌是已知唯一能产生超抗原（假结核耶尔森菌衍生丝裂原[YPM]）的革兰氏阴性菌。这种超抗原与抗原呈递细胞上的主要组织相容性复合体II类分子以及带有可变区Vβ3、Vβ9、Vβ13.1或Vβ13.2（在人类中）和Vβ7或Vβ8（在小鼠中）的T细胞受体（TcR）结合。我们之前已经表明，YPM会加剧假结核耶尔森菌在小鼠中的毒力。为了了解YPM毒性的机制，我们比较了感染产生YPM的假结核耶尔森菌或相应的同基因、超抗原缺陷突变体的BALB/c小鼠的免疫反应。感染后五天，我们观察到接种产生超抗原的假结核耶尔森菌的小鼠中CD4(+) Vβ7(+) T细胞强烈扩增以及显著的白细胞介素-4（IL-4）产生。这些现象与肝脏和脾脏中ypm基因转录的激活相关。转录组分析显示，YPM的存在还增加了宿主肝脏和脾脏中颗粒酶和穿孔素基因的表达。这种表达归因于CD4(+) T细胞亚群，而不是归因于具有可能被YPM识别的Vβ区域的TcR的自然杀伤T（NKT）细胞。细胞毒性分子产生的增加与肝毒性相关，血浆丙氨酸转氨酶活性的增加证明了这一点。我们的结果表明，YPM激活了潜在的肝毒性CD4(+) T细胞群体。
