Deciphering the signals regulating flu-specific resident memory T cells

描述（由申请人提供）：流感病毒的季节性流行每年在美国导致200，000例住院和36，000例死亡。目前的流感疫苗引发针对表面糖蛋白的抗体应答。 然而，高突变率使流感病毒能够逃避预先存在的抗体的中和。 此外，流感疫苗在老年人群中的有效性大大降低。因此，设计能够提供针对流感病毒的持久和广泛保护的疫苗至关重要。能够诱导记忆性CD8 T细胞的疫苗由于其识别来自内部病毒蛋白的表位的能力而受到特别关注 在菌株间高度保守的基因然而，一种基于CD8 T细胞的疫苗，提供持久的保护，对流感尚未开发，部分原因是有足够的知识的形成和维持记忆T细胞在肺粘膜。该提案旨在深入了解肺驻留记忆T（TRM）细胞形成所需的信号，这些细胞被认为能够提供针对流感病毒的保护。我们假设，CD4帮助和促炎和抗炎信号的最佳平衡对于肺驻留记忆CD8 T细胞的形成至关重要。提出了三个具体目标来质疑这一假设。第一个目的是通过耗尽CD4 T细胞来确定在肺驻留记忆形成中对CD4帮助的需求。将在存在和不存在CD4 T细胞的情况下测量趋化因子和细胞因子水平，以评估CD4辅助的机制。第二个目标将评估的TGF？和T-bet信号轴在肺CD8 TRM细胞形成中的作用以及该通路是否可以通过调节炎症暴露程度来控制TRM的形成。第三个目标将确定老化对TRM形成的影响，并测试在老年人中发现的炎症环境增加导致TRM细胞形成减少的假设。总而言之，该提案旨在深入了解TRM形成所需的信号，理解这些信号的进一步知识将有助于开发能够提供针对流感病毒的持久保护的疫苗。此外，该申请详细说明了申请人的培训计划，包括研究指导，高级课程，新技术培训以及科学专业，写作和数据展示技能的发展。本申请中概述的研究和培训将使申请人能够作为独立科学家从事临床相关研究。

DESCRIPTION (provided by applicant): Seasonal epidemics of the influenza virus result in 200,000 hospitalizations and 36,000 deaths each year in the United States. Current influenza vaccines elicit an antibody response against the surface glycoproteins. However, high mutation rates allow the influenza virus to evade neutralization by preexisting antibodies. Furthermore, influenza vaccines have greatly reduced effectiveness among the elderly population. Therefore, it is of critical importance to design a vaccine capable of providing long-lasting and broad protection against the influenza virus. A vaccine capable of inducing memory CD8 T cells has been of particular interest due to their ability to recognize epitopes from internal viral proteins that are highly conserved among strains. However, a CD8 T-cell based vaccine that provides lasting protection against flu has yet to be developed in part because there is insufficient knowledge of formation and maintenance of memory T cells in lung mucosa. This proposal seeks to provide insight into the signals necessary for the formation of lung resident memory T (TRM) cells that are thought to be capable of providing protection against the influenza virus. We hypothesize that CD4 help and an optimal balance of pro and anti-inflammatory signals is crucial for the formation of lung resident memory CD8 T cells. Three specific aims are proposed to interrogate this hypothesis. The first aim seeks to determine the requirement for CD4 help in the formation of lung resident memory through depletion of CD4 T cells. Chemokine and cytokine levels will be measured in the presence and absence of CD4 T cells to assess the mechanism of CD4 help. The second aim will evaluate the importance of the TGF? and T-bet signaling axis in lung CD8 TRM cell formation and whether this pathway can control TRM formation through modulation of the degree of inflammatory exposure. The third aim will determine the effect of aging on TRM formation and test the hypothesis that the increased inflammatory environment found in aged individuals acts leads to reduced formation of TRM cells. Altogether, this proposal seeks to provide insight into the signals necessary for TRM formation with the understanding that further knowledge of these signals will aid in the development of vaccines capable of providing long lasting protection against the influenza virus. In addition, this application details the applicant's training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of clinically relevant research as an independent scientist.