Memory CD8 T cell localization and protection from influenza

记忆 CD8 T 细胞定位和流感保护

• 批准号: 8960855
• 负责人: VLADIMIR P BADOVINAC
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960855
• 关键词: Address; Affect; Antibodies; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; CXCR3 gene; Cell Count; Cells; Characteristics; Collaborations; Data; Disease; Epitopes; Exposure to; Gene Expression; Generations; Goals; Health; Hemagglutinin; Human; Immunity; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Information Protection; Interleukin-12; Location; Longitudinal Studies; Mediating; Memory; Modeling; Molecular; Mutate; Mutation; Neuraminidase; Nucleoproteins; Paper; Pathway interactions; Polymerase; Population; Population Heterogeneity; Productivity; Property; Proteins; Publishing; Reporting; Research Personnel; STAT4 gene; Signal Transduction; Surveys; T memory cell; T-Cell Activation; T-Lymphocyte; Tissues; Transcend; Vaccination; Vaccines; Viral Proteins; Virus Diseases; cross immunity; design; influenzavirus; neutralizing antibody; novel strategies; pandemic disease; response

DESCRIPTION (provided by applicant): Influenza virus infections have a major impact on human health and the threat of pandemic infections remains imminent. Antibody inducing Influenza A virus (IAV) vaccines are available, however protection is suboptimal and requires annual reformulation of the vaccine. IAV can escape neutralization by preexisting antibodies due to the high rate of mutation in the primary targets of neutralization (hemagglutinin, HA and neuraminidase, NA) and due to its capacity to recombine in non-human hosts. In the absence of neutralizing antibodies, memory CD8 T-cell specific for epitopes located in conserved regions of IAV proteins like the internal components nucleoprotein (NP), polymerase A and matrix protein can confer protection. Recent human challenge studies and longitudinal analyses during the 2009 H1N1 IAV pandemic support the notion that cross-reactive memory CD8 T cells are capable of ameliorating disease when pre-existing antibodies are absent. As most humans carry a small number of these broadly protective memory CD8 T-cells, increasing the number of these cells through boosting is an attractive strategy to bolster their protective capacity. However, memory CD8 T-cells constitute a very heterogeneous population and little is known about how boosting or multiple antigen exposures effects CD8 T-cell mediated protection against IAV, For instance, we have recently reported that the type of booster agent significantly affects the localization and protective capacity of the resulting memory CD8 T-cell population (Sl�tter et al, 2013). Therefore, our long-term goal is to determine optimal memory CD8 T-cell characteristics for protection against IAV and to understand how such memory populations can be generated. In turn, these studies will provide crucial information to optimize broadly protective vaccines for IAV. Specific Aim 1. Determine the molecular mechanisms regulating CXCR3 expression in memory CD8 T cells to enhance airway localization. Specific Aim 2. Determine the impact of repetitive IAV infections on the generation of airway---surveilling, tissue resident and circulatin memory CD8 T cells and their relative contribution in protection from IAV.

描述（由申请人提供）：流感病毒感染对人类健康产生重大影响，大流行感染的威胁仍然迫在眉睫。可以使用诱导甲型流感病毒 (IAV) 的抗体疫苗，但保护效果欠佳，并且需要每年重新配制疫苗。由于主要中和靶标（血凝素、HA 和神经氨酸酶、NA）的突变率很高，并且 IAV 能够在非人类宿主中重组，因此 IAV 可以逃避预先存在的抗体的中和作用。在没有中和抗体的情况下，记忆 CD8 T 细胞对位于 IAV 蛋白保守区域（如内部成分核蛋白 (NP)、聚合酶 A 和基质蛋白）的表位具有特异性，可以提供保护。最近的人类挑战研究和 2009 年 H1N1 IAV 大流行期间的纵向分析支持这样的观点：当预先存在的抗体不存在时，交叉反应记忆 CD8 T 细胞能够改善疾病。由于大多数人携带少量具有广泛保护作用的记忆 CD8 T 细胞，因此通过加强免疫来增加这些细胞的数量是增强其保护能力的一种有吸引力的策略。然而，记忆 CD8 T 细胞构成了一个非常异质的群体，并且对于加强或多次抗原暴露如何影响 CD8 T 细胞介导的 IAV 保护作用知之甚少，例如，我们最近报道，加强剂的类型显着影响所得记忆 CD8 T 细胞群体的定位和保护能力 (Slütter 等，2013)。因此，我们的长期目标是确定最佳记忆 CD8 T 细胞特征以预防 IAV，并了解如何生成此类记忆群体。反过来，这些研究将为优化具有广泛保护性的疫苗提供重要信息 IAV。具体目标 1. 确定调节记忆 CD8 T 细胞中 CXCR3 表达以增强气道定位的分子机制。 具体目标 2. 确定重复 IAV 感染对气道生成的影响——监视、组织驻留和循环记忆 CD8 T 细胞及其在预防 IAV 方面的相对贡献。