Visualizing invariant NKT cell dynamics following immunization and infection

描述(申请人提供)：存活的系统性感染需要驻留在脾中的先天免疫细胞的快速和有力的反应。事实上，切除脾的人类和啮齿动物比正常人更容易死于系统性细菌感染。脾免疫隔间的一个重要组成部分是不变自然杀伤T细胞(INKT)，这是一种识别自身和病原体来源的脂类抗原的独特的固有淋巴细胞谱系。在激活的几个小时内，iNKT细胞迅速产生效应器反应，介导对许多感染源的保护，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发挥作用，但对脾iNKT细胞激活的细胞需求和功能影响在很大程度上是未知的。结合一种新的原位追踪内源性iNKT细胞群体的方法和各种基因缺失和细胞耗尽技术，这项建议中的研究将揭示肺炎球菌感染后iNKT细胞效应程序制定所需的定位和抗原提呈细胞。此外，我们将确定iNKT细胞激活与肺炎链球菌早期保护性体液反应的相关性。这些研究将极大地促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iNKT在感染和炎症过程中的动态变化奠定基础。 公共卫生相关性：全身性细菌感染引起的败血症仍然是全球范围内死亡的主要原因。尽管在预防这些入侵病原体的疫苗方面取得了重大进展，但耐药菌株仍在继续出现，并对全球医疗体系产生负面影响。为了更有效地抗击这些感染，需要更好地了解所涉及的免疫细胞类型及其调节感染抵抗力的机制。这些研究产生的数据将大大提高我们对系统性细菌感染免疫的最早事件的了解，并有助于设计更有效的抗菌疗法。

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. PUBLIC HEALTH RELEVANCE: Sepsis resulting from systemic bacterial infections remains a major cause of mortality worldwide. Despite significant progress in vaccines designed to protect against these invasive pathogens, drug-resistant strains continue to emerge and negatively impact the global healthcare system. To more effectively combat these infections, a greater understanding of the immune cell types involved and the mechanisms by which they mediate resistance to infection are needed. The data generated from these studies will significantly advance our knowledge of the earliest events in immunity to systemic bacterial infection and facilitate the design of more effective anti-bacterial therapeutics.