CD8 T Cell Response to Influenza Virus Infection

CD8 T 细胞对流感病毒感染的反应

• 批准号: 7391518
• 负责人: Leo Lefrancois
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391518
• 关键词: Anatomy; Antigens; B-Lymphocytes; Behavior; CD8B1 gene; Categories; Cells; Characteristics; Data; Depth; Development; Effectiveness; Event; Foundations; Health; Human; Imagery; Immune; Immune response; Immunity; In Situ; Infection; Infectious Agent; Knowledge; Learning; Light; Link; Localized; Location; Mediating; Memory; Molecular; Morbidity - disease rate; PTPRC gene; Phenotype; Population; Role; Serotyping; Site; Spleen; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Vaccination; Viral; Virus Diseases; base; biodefense; genetically engineered virus; in vivo; influenzavirus; lymph nodes; mortality; neutralizing antibody; novel; pandemic disease; pathogen; research study; response

DESCRIPTION (provided by applicant): Influenza virus, a Category C Biodefense pathogen, is a clinically important infectious agent with serious implications for human health. The threat of a pandemic as well as the potential for intentional contamination with highly pathogenic or genetically engineered virus strains provide strong rationales for further in-depth analysis of the immune mechanisms of viral control, the focus of this RFA. While vaccination against infection is believed to be mediated primarily by induction of serotype-specific neutralizing antibody, CD8 T cells have the potential to provide broad-based effectiveness against distinct viral serotypes. Our preliminary data identifies a novel memory CD8 T cell subset and suggests a potential link between memory CD8 T cells and B cells. These findings provide the foundation for this proposal aimed at learning the functional significance of the anatomical localization of memory CD8 T cell subsets and determining their protective capacity against influenza virus infection. The specific aims of the proposal are: Specific Aim 1. To characterize memory CD8 T cell subsets and determine their protective ability following influenza virus infection. The memory CD8 T cell population that develops following influenza virus infection is heterogeneous and comprised of multiple subsets based on phenotype and location. Our preliminary data suggested additional complexity by identifying a novel B220+ memory CD8 T cell subset. Experiments in this aim will focus on an in-depth phenotypic and functional characterization of memory CD8 T cell subsets including testing their ability to mount secondary responses and provide protection against influenza virus infection. Specific Aim 2. To visualize the primary and recall response to influenza virus infection in situ. The anatomical events that occur in situ during the immune response to primary or secondary influenza virus infection have not been described. We have developed techniques to allow visualization of endogenous antigen-specific primary and memory CD8 T cells in situ following infection. Preliminary data identify a novel population of memory CD8 T cells residing in the B cell zones of the lymph nodes and spleen following influenza virus infection and whether B220+ memory cells preferentially localize to these sites will be tested. The behavior of this population and other memory subsets to respond to infection will also be determined. In this way, a link will be established between the protective capacity of memory subsets and the anatomy of the secondary response. Overall, these studies will fill a significant gap in our knowledge regarding the role of memory CD8 T cells in controlling influenza virus infection.

描述（由申请人提供）：流感病毒是一种 C 类生物防御病原体，是一种临床上重要的传染原，对人类健康具有严重影响。大流行的威胁以及高致病性或基因工程病毒株故意污染的可能性，为进一步深入分析病毒控制的免疫机制提供了强有力的理由，这也是本次 RFA 的重点。虽然针对感染的疫苗接种被认为主要是通过诱导血清型特异性中和抗体介导的，但 CD8 T 细胞有潜力针对不同的病毒血清型提供广泛的有效性。我们的初步数据确定了一种新的记忆 CD8 T 细胞亚群，并表明记忆 CD8 T 细胞和 B 细胞之间存在潜在联系。这些发现为该提案奠定了基础，该提案旨在了解记忆 CD8 T 细胞亚群的解剖定位的功能意义并确定其针对流感病毒感染的保护能力。该提案的具体目标是： 具体目标 1. 表征记忆 CD8 T 细胞亚群并确定其在流感病毒感染后的保护能力。流感病毒感染后形成的记忆 CD8 T 细胞群是异质的，由基于表型和位置的多个亚群组成。我们的初步数据表明，通过识别新型 B220+ 记忆 CD8 T 细胞子集，会带来额外的复杂性。这一目标的实验将重点关注记忆 CD8 T 细胞亚群的深入表型和功能表征，包括测试它们发起二次反应和提供针对流感病毒感染的保护的能力。 具体目标 2. 直观地想象对流感病毒感染的原位反应并回忆其反应。尚未描述在对原发性或继发性流感病毒感染的免疫反应期间原位发生的解剖学事件。我们开发了技术，可以在感染后原位观察内源性抗原特异性初级和记忆 CD8 T 细胞。初步数据确定了流感病毒感染后，存在于淋巴结和脾脏 B 细胞区的新型记忆 CD8 T 细胞群，并将测试 B220+ 记忆细胞是否优先定位于这些部位。该群体和其他记忆子集对感染的反应行为也将被确定。通过这种方式，将在记忆子集的保护能力和次级反应的解剖结构之间建立联系。总体而言，这些研究将填补我们关于记忆 CD8 T 细胞在控制流感病毒感染中的作用的知识空白。