T Cell Memory to Pathogens: Generation and Function

“生成和功能。“我们提出了一个综合计划来分析CD 4和CD 8 T细胞记忆对引起流感（流感）和结核病（TB）的呼吸道病原体的影响。在复杂的动物模型中，我们将定义CD 4和CD 8记忆T细胞的亚群，并确定其产生，功能，位置，持久性和与其他T细胞亚群的关系的细胞和分子基础。这将大大扩展我们对免疫的基本理解。 “CD 4记忆亚群的产生和持续性”（Swain）将确定CD 4 T细胞的不同功能亚群的关系，并将确定它们是否成为功能性的记忆亚群并定义它们的保护功能。他们将分离出效应和记忆CD 4 T细胞的亚群，这些细胞通过杀死受感染的靶细胞起作用，并将它们与那些引起炎症并分泌炎性因子IL-17的细胞以及那些通过帮助B细胞起作用的细胞进行比较。 “CD 8记忆T细胞保护机制”（达顿）将确定CD 8 T细胞亚群使用的机制，该机制与项目1中的CD 4亚群使用的机制相似。特别是，他们将研究产生IL-17的CD 8 T细胞亚群，他们的初步数据显示这些亚群在预防流感中起着关键作用，并将这些Tc 17与Tc 1亚群进行比较，并确定它们的功能和保护能力以及作用机制。 “T细胞稳态和记忆的调节”（布拉德利）将确定来自肺细胞上表达的“选择素”的信号是否控制CD 4和CD 8 T细胞应答，并且是否是CD 4记忆细胞的发育和持续所需的。他们将确定选择素结合能力是否识别CD 4细胞的不同功能子集，以及哪些CD 4反应是选择素依赖的。 “肺中TB的T细胞记忆”（库珀）将确定调节保护性记忆性CD 4 T细胞，特别是Th 17亚群的诱导的因子。他们还将检查肺中调节记忆T细胞功能表达的因素，并确定调节肺中的IL-17记忆反应是否可以增加保护作用。 定义记忆T细胞亚群提供保护性免疫的机制，可能会导致识别流感和结核病保护的新相关性，这将为未来的疫苗提供信息，这些疫苗除了抗体外，还旨在诱导强大的T细胞记忆，因此即使出现结核病和流感的新菌株，包括大流行性流感，免疫也将有效。

"Generation and Function." We propose an integrated program to analyze CD4 and CD8 T cell memory against the respiratory pathogens causing influenza (flu) and tuberculosis (TB). In sophisticated animal models, we will define subsets of CD4 and CD8 memory T cells and determine the cellular and molecular basis of their generation, functions, location, persistence and relationship to other T cell subsets. This will greatly extend our basic understanding of immunity. "Generation and Persistence of CD4 Memory Subsets" (Swain), will determine the relationships of different functional subsets of CD4 T cells and will determine if they become functionally committed subsets of memory and define their protective functions. They will separate subsets of effector and memory CD4 T cells that work by killing infected targets and compare them to those that cause inflammation and secrete an inflammatory factor IL-17, and those that act by helping B cells. "CD8 Memory T Cells Mechanisms of Protection" (Dutton) will identify the mechanisms used by the CD8 T cell subsets that parallel those in Project 1 for CD4 subsets. In particular they will study the IL-17 producing subset of CD8 T cells that their preliminary data show plays a key role in protection against influenza, and compare these Tc17 to Tc1 subsets and define their function and protective abilities and mechanisms of action. "Regulation Of T Cell Homeostasis and Memory" (Bradley), will determine whether signals from "selectins" expressed on lung cells control CD4 and CD8 T cell responses and are needed for the development and persistence of CD4 memory cells. They will determine if selectin binding capacity identifies a distinct functional subset of CD4 cells, and what CD4 responses are selectin-dependent. "T Cell Memory to TB in the Lung" (Cooper), will determine factors that regulate induction of protective memory CD4 T cells, especially of the Th17 subset. They will also examine factors in the lung that regulate expression of memory T cell function in the lung and determine whether modulating the IL-17 memory response in the lung can increase protection. Defining the mechanisms by which memory T cell subsets provide protective immunity, is likely to result in identification of new correlates of protection for flu and TB, that will inform future vaccines targeted towards inducing robust T cell memory in addition to antibody, so that immunization will be effective even when new strains of TB and flu, including pandemic flu, emerge.