Deciphering the signals regulating flu-specific resident memory T cells

描述(申请人提供)：流感病毒的季节性流行在美国每年导致200,000人住院和36,000人死亡。目前的流感疫苗可引起针对表面糖蛋白的抗体反应。然而，高突变率允许流感病毒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，设计一种能够对流感病毒提供持久和广泛保护的疫苗至关重要。由于能够识别内部病毒蛋白的表位，一种能够诱导记忆CD8 T细胞的疫苗引起了人们的特别兴趣 在菌株间高度保守。然而，一种基于CD8 T细胞的疫苗还没有开发出来，这种疫苗可以提供对流感的持久保护，部分原因是对肺粘膜中记忆T细胞的形成和维护了解不足。这项建议旨在洞察肺常驻记忆T细胞(TRM)的形成所需的信号，这些细胞被认为能够提供对流感病毒的保护。我们假设，CD4的帮助以及促炎和抗炎信号的最佳平衡对肺常驻记忆CD8T细胞的形成至关重要。本文提出了三个具体目标来验证这一假说。第一个目的是通过耗尽CD4T细胞来确定在肺驻留记忆的形成中对CD4的帮助的需求。趋化因子和细胞因子水平将在有无CD4T细胞的情况下进行测量，以评估CD4HELP的机制。第二个目的是评估转化生长因子的重要性？以及T-bet信号轴在肺CD8 TRM细胞形成中的作用，以及该途径是否可以通过调节炎症暴露的程度来控制TRM的形成。第三个目标将确定衰老对TRM形成的影响，并检验老年人ACTs中发现的炎性环境增加导致TRM细胞形成减少的假设。总之，这项建议旨在深入了解TRM形成所需的信号，并理解对这些信号的进一步了解将有助于开发能够对流感病毒提供长期保护的疫苗。此外，这份申请详细说明了申请者的培训计划，包括研究指导、高级课程工作、新技术培训以及科学专业精神、写作和数据展示方面的技能发展。申请书中概述的研究和培训将使申请者做好准备，以独立科学家的身份从事临床相关研究。

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.