Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612, USA.
J Immunol. 2012 Aug 1;189(3):1285-93. doi: 10.4049/jimmunol.1200641. Epub 2012 Jun 27.
Although Listeria monocytogenes can induce systemic infection causing spontaneous abortion, septicemia, and meningitis, studies have not been performed to investigate human anti-L. monocytogenes immune responses, including those of Ag-specific Vγ2Vδ2 T cells, a dominant human γδ T cell subset. L. monocytogenes is the only pathogen known to possess both the mevalonate and non-mevalonate isoprenoid biosynthesis pathways that produce metabolic phosphates or phosphoantigens activating human Vγ2Vδ2 T cells, making it interesting to explore in vivo anti-L. monocytogenes immune responses of Vγ2Vδ2 T cells. In this study, we demonstrated that subclinical systemic L. monocytogenes infection of rhesus macaques via parenteral inoculation or vaccination with an attenuated Listeria strain induced multieffector-functional immune responses of phosphoantigen-specific Vγ2Vδ2 T cells. Subclinical systemic infection and reinfection with attenuated L. monocytogenes uncovered the ability of Vγ2Vδ2 T cells to mount expansion and adaptive or recall-like expansion. Expanded Vγ2Vδ2 T cells could traffic to and accumulate in the pulmonary compartment and intestinal mucosa. Expanded Vγ2Vδ2 T cells could evolve into effector cells producing IFN-γ, TNF-α, IL-4, IL-17, or perforin after L. monocytogenes infection, and some effector Vγ2Vδ2 T cells could coproduce IL-17 and IFN-γ, IL-4 and IFN-γ, or TNF-α and perforin. Surprisingly, in vivo-expanded Vγ2Vδ2 T effector cells in subclinical L. monocytogenes infection could directly lyse L. monocytogenes-infected target cells and inhibit intracellular L. monocytogenes bacteria. Thus, we present the first demonstration, to our knowledge, of multieffector-functional Vγ2Vδ2 T cell responses against L. monocytogenes.
虽然李斯特菌可以引起全身性感染，导致自然流产、败血症和脑膜炎，但尚未研究人类针对李斯特菌的免疫反应，包括 Ag 特异性 Vγ2Vδ2 T 细胞，这是一种主要的人类 γδ T 细胞亚群。李斯特菌是唯一已知同时拥有甲羟戊酸和非甲羟戊酸异戊烯醇生物合成途径的病原体，该途径产生代谢磷酸盐或磷酸抗原，激活人类 Vγ2Vδ2 T 细胞，因此研究李斯特菌的体内抗李斯特菌免疫反应非常有趣。在这项研究中，我们证明了通过静脉内接种或用减毒李斯特菌株进行疫苗接种对恒河猴进行亚临床全身性李斯特菌感染，会诱导磷酸抗原特异性 Vγ2Vδ2 T 细胞的多效性功能免疫反应。亚临床全身性感染和用减毒李斯特菌再次感染揭示了 Vγ2Vδ2 T 细胞的扩增和适应性或回忆样扩增的能力。扩增的 Vγ2Vδ2 T 细胞可以迁移并在肺和肠道黏膜中积聚。扩增的 Vγ2Vδ2 T 细胞在李斯特菌感染后可以演变成产生 IFN-γ、TNF-α、IL-4、IL-17 或穿孔素的效应细胞，一些效应 Vγ2Vδ2 T 细胞可以共同产生 IL-17 和 IFN-γ、IL-4 和 IFN-γ 或 TNF-α和穿孔素。令人惊讶的是，在亚临床李斯特菌感染中体内扩增的 Vγ2Vδ2 T 效应细胞可以直接裂解李斯特菌感染的靶细胞并抑制细胞内李斯特菌细菌。因此，我们首次证明了针对李斯特菌的多效性功能 Vγ2Vδ2 T 细胞反应。
