Solaymani-Mohammadi Shahram, Lakhdari Omar, Minev Ivelina, Shenouda Steve, Frey Blake F, Billeskov Rolf, Singer Steven M, Berzofsky Jay A, Eckmann Lars, Kagnoff Martin F
*Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA
*Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
J Leukoc Biol. 2016 Mar;99(3):475-82. doi: 10.1189/jlb.4A0115-003RR. Epub 2015 Oct 14.
The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.
程序性死亡-1受体在多种免疫效应细胞上表达，包括T细胞、自然杀伤T细胞、树突状细胞、巨噬细胞和自然杀伤细胞。在恶性肿瘤和慢性病毒感染中，T细胞上程序性死亡-1表达增加通常与预后不良相关。然而，其在肠道黏膜早期宿主微生物防御中的作用尚不清楚。我们报告，感染小鼠病原体鼠柠檬酸杆菌后，传统自然杀伤细胞上程序性死亡-1表达增加，但CD4(+)、CD8(+)或自然杀伤T细胞，或CD11b(+)或CD11c(+)巨噬细胞或树突状细胞上的程序性死亡-1表达未增加。程序性死亡-1基因缺陷的小鼠或用抗程序性死亡-1抗体处理的小鼠对鼠柠檬酸杆菌的急性肠道和全身感染更易感。感染鼠柠檬酸杆菌的野生型小鼠而非程序性死亡-1缺陷型小鼠显示传统黏膜自然杀伤细胞效应分子颗粒酶B和穿孔素的表达显著增加。相比之下，程序性死亡-1缺陷型小鼠的自然杀伤细胞中这些介质的表达受损。与程序性死亡-1对自然杀伤细胞效应分子细胞内表达很重要一致，自然杀伤细胞耗竭的小鼠和穿孔素缺陷型小鼠对鼠柠檬酸杆菌的急性肠道感染易感性增加。我们的研究结果表明，传统自然杀伤细胞中程序性死亡-1信号通路表达增加，通过增强自然杀伤细胞功能重要效应分子的表达和产生，在细菌肠道病原体急性感染期间促进肠道黏膜的宿主保护。
