Elucidation of the role of Vα14+NKT cells during infection with various microbial pathogens and application of medical treatment

研究了细菌感染过程中小鼠肝脏糖脂/CD 1d反应性Vα 14 ^+ T细胞的表型和功能变化。在单核细胞增生李斯特菌感染或IL-12治疗后，在正常胸腺和胸腺切除的动物中，在感染的早期阶段，α-半乳糖神经酰胺/CD 1d四聚体反应性（α-GalCer/CD 1d ^+）T细胞共表达NK1.1标记物变得不可检测，同时出现缺乏NK1.1的细胞。NK1.1亚群的耗竭阻止了α-GalCer/CD 1d ^+ NK1.1^- T细胞的出现。感染前，共表达CD 4的NK 1.1 ^+、而不是NK 1.1 ^-、α-GalCer/CD 1d ^+ T细胞负责IL-4的产生，而IFN-γ则由细胞产生，而不管NK 1.1或CD 4的表达如何。感染后，在α-GalCer/CD 1d ^+ T细胞中检测不到IL-A分泌细胞，但在NK1.1细胞中发现了相当数量的IFN-γ分泌细胞，但在缺乏CD 4的NK1.1^+细胞中没有发现。因此，NK1.1的表面表达和功能活性， ...更多信息 Vα 14 ^+ T细胞在胸腺增生的早期阶段发生了显著变化，这些变化以不依赖胸腺的方式进行。在缺乏所有α-GalCer/CD 1d ~^+T细胞的突变小鼠中，骨髓增生得到了改善，这表明NK1.1^-T细胞亚群对抗菌保护的细微贡献被NK1.1^+ T细胞亚群更深刻的有害作用所掩盖。在随后的时间点，NK1.1^- iNKT细胞群收缩，而NK1.1^+ iNKT细胞重新出现。iNKT细胞的NK1.1表面表达的改变被肝脏中IL-12产生者的数量变化所抑制，并被内源性IL-12中和完全阻止，而α-GalCer刺激后iNKT细胞上的NK1.1表面改变未被阻止。连续细胞转移实验显示，来自单核细胞增生李斯特菌感染小鼠的肝脏NK1.1^- iNKT细胞在受体重组激活基因-1缺陷小鼠的肝脏中积累，在那里它们获得NK1.1表面表达，这表明在单核细胞增生李斯特菌感染期间，肝脏iNKT细胞上的NK1.1表面表达是可逆的，并且TCR和IL-12刺激的机制不同。α-GalCer处理显著抑制单核细胞增生李斯特菌感染后肝脏和脾脏中的细菌生长和炎症。α-GalCer处理加速了粒细胞和γ/δ T细胞的肝脏浸润，这些细胞的消耗加重了线粒体病。我们的研究结果表明，α-GalCer诱导抗菌免疫，部分原因是炎症细胞加速浸润到肝脏中。少

The phenotypic and functional changes of glycolipid/CD1d-reactive Vαl4^+ T cells in the liver of mice during bacterial infection were investigated. After Listeria monocytogenes infection or IL-12 treatment, α-galactosylceramide/CD1d tetramer-reactive (α-GalCer/CD1d^+) T cells coexpressing NK1.1 marker became undetectable and concomitantly cells lacking NK1.1 emerged in both euthymic and thymectomized animals at early stages of infection. Depletion of the NK1.1 subpopulation prevented the emergence of α-GalCer/CD1d^+ NK1.1^- T cells. Before infection, NK1.1^+, rather than NK1.1^-, α-GalCer/CD1d^+ T cells coexpressing CD4 were responsible for IL-4 production, whereas IFN-γ was produced by cells regardless of NK1.1 or CD4 expression. After infection, IL-A-secreting cells became undetectable among α-GalCer/CD1d^+ T cells, but considerable numbers of IFN-γ-secreting cells were found among NK1.1, but not NK1.1^+, cells lacking CD4. Thus, NK1.1 surface expression and functional activities of … More Vαl4^+ T cells underwent dramatic changes at early stages of listeriosis and these alterations progressed in a thymus-independent manner. In mutant mice lacking all α-GalCer/CD1d~^+T cells, listeriosis was ameliorated, suggesting that subtle contribution of the NK1.1^-T-cell subset to antibacterial protection is covered by more profound detrimental effects of the NK1.1^+T-cell subset. At later time points, the NK1.1^- iNKT cell population contracted, whereas NK1.1^+ iNKT cells reemerged. Alterations in NK1.1 surface expression of iNKT cells were paralleled by numerical changes of IL-12 producers in the liver and were completely prevented by endogenous IL-12 neutralization, whereas NK1.1 surface alterations on iNKT cells following α-GalCer stimulation were not prevented. Adoptive cell transfer experiments revealed that the liver NK1.1^- iNKT cells from L.monocytogenes-infected mice accumulated in the liver of recipient recombination-activating gene-1-deficient mice where they acquired NK1.1 surface expression, suggesting that NK1.1 surface expression on liver iNKT cells is reversible during L.monocytogenes infection, and that different mechanisms underlie stimulation by TCR and IL-12. Bacterial growth and inflammation in the liver and spleen following Listeria monocytogenes infection were dramatically inhibited by α-GalCer treatment. Liver infiltration of granulocytes and γ/δ T cells was accelerated by α-GalCer treatment, and depletion of these cells exacerbated listeriosis. Our results indicate that α-GalCer induces antibacterial immunity caused, in part, by accelerated infiltration of inflammatory cells into the liver. Less