Visualizing invariant NKT cell dynamics following immunization and infection

描述（由申请人提供）：全身性感染的存活需要脾脏中固有免疫细胞的快速和强烈反应。事实上，脾切除的人类和啮齿动物比正常个体更容易死于全身性细菌感染。脾脏免疫区室的一个突出组成部分是不变的自然杀伤T（iNKT）细胞，一种独特的先天淋巴细胞谱系，识别自身以及病原体衍生的脂质抗原。在激活数小时内，iNKT细胞迅速发挥效应反应，介导对许多感染因子的保护，包括革兰氏阳性细菌肺炎链球菌，这是社区获得性肺炎最常见的原因。尽管它们在抗菌免疫中的作用，脾iNKT细胞活化的细胞要求和功能意义在很大程度上是未知的。结合一种新的方法来跟踪内源性iNKT细胞群体原位与各种基因缺失和细胞耗竭技术，在这个建议中的研究将揭示定位和抗原呈递细胞所需的阐述的iNKT细胞效应程序后肺炎球菌感染。此外，我们还将确定iNKT细胞活化与S.肺炎。这些研究将大大推进我们对先天免疫系统细胞之间复杂相互作用的理解，并为未来研究感染和炎症期间iNKT功能的动态奠定基础。

DESCRIPTION (provided by applicant): Surviving systemic infection requires a rapid and vigorous response by innate immune cells residing in the spleen. Indeed, splenectomized humans and rodents are more likely to succumb to systemic bacterial infections than normal individuals. A prominent component of the splenic immune compartment are invariant natural killer T (iNKT) cells, a distinct lineage of innate lymphocytes that recognize self as well as pathogen-derived lipid antigens. Within hours of activation, iNKT cells rapidly exert an effector response that mediates protection against a number of infectious agents including the gram-positive bacteria Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Despite their role in antibacterial immunity, the cellular requirements for and functional implications of splenic iNKT cell activation are largely unknown. Combining a novel method to track the endogenous iNKT cell population in situ with various genetic deletion and cell depletion techniques, the studies in this proposal will reveal the localization and antigen-presenting cells required for elaboration of the iNKT cell effector program following pneumococcal infection. Furthermore, we will determine the relevance of iNKT cell activation in terms of the early protective humoral response to S. pneumoniae. These studies will significantly advance our understanding of the complex interplay between cells of the innate immune system and set the stage for future studies investigating the dynamics of iNKT function during infection and inflammation.