Generation and persistence of CD4 memory subsets

CD 4记忆子集的生成与持久性 最近，我们发现流感特异性CD 4 T细胞效应器通过其自身的免疫功能提供了抵抗致命攻击的保护作用。 直接溶细胞活性（ThCTL）和抗体的帮助，表明额外的功能异质性 可能导致CD 4记忆异质性，并帮助我们发现新的 疫苗诱导的保护机制。我们最近有证据表明，IL-17产生的CD 4也发挥作用， 在抗击流感中的作用。我们的目标是评估ThCTL细胞代表一种独特的免疫应答的假设。 Th 1和Th 7参与有效免疫应答的功能特化亚群。我们将 在效应子阶段比较ThCTL与Th 7和Thi子集，以进一步确定它们各自的功能 并确定它们是如何保护肺部免受流感侵袭的。我们将询问ThCTL和Thi 7是否给出 提升到特定的记忆子集，并决定它们在对抗流感中的作用。 为了实现这些目标，我们将：1）分离体外产生的确定的CD 4效应子亚群，并开发一种新的CD 4效应子亚群。 当它们在体内发育时，计划将它们分离。我们将确定他们的细胞因子和趋化因子谱， 它们的迁移和它们参与帮助、细胞毒性和保护免受流感的攻击。我们 将使用功能简介为每个子集开发“签名”; 2)我们将确定每个子集产生记忆细胞的能力，这些记忆细胞对挑战做出反应， 并询问它们是否保留了相同的功能潜力， 区分;以及3）我们将评估每个存储器Th子集用于提供保护的机制 对抗致命流感的挑战 我们将与以下项目合作：1）项目2，以确定CD 4亚群与平行CDS的比较情况 2）项目3，以确定CD 4亚群的迁移，以及在 肺以及与选择素的相互作用如何调节效应器的功能和记忆产生; 3）项目 4.研究相似的抗原特异性CD 4亚群是否可以提高抗 肺结核感染。 相关性（参见说明）： 目前的流感疫苗是基于对每年变化的外壳蛋白特异性抗体的诱导， 所以它们只能提供短期保护。了解记忆T细胞提供 免疫，应该提出新的CD 4 T细胞相关的保护，并提供见解，可用于 开发改进疫苗的新策略，可以针对诱导强大的T细胞 记忆，除了抗体，使免疫将更加有效和持久。

Generation and Persistence of CD4 Memory Subsets Recently we found that flu-specific CD4 T cell effectors provide protection against lethal challenge by virtue of both direct cytolytic activity (ThCTL) and help for Ab, suggesting additional functional heterogeneity among CD4 subsets that may contribute to CD4 memory heterogeneity and help us uncover new mechanisms of vaccine-induced protection. We have recent evidence that IL-17 producing CD4 also play a role in combating influenza. Our goal here is to evaluate the hypothesis that ThCTL cells represent a distinct functionally specialized subset that with Thi and Thi7 participate in an effective immune response. We will compare ThCTL to Thi7 and Thi subsets at the effector stage to further define their respective functions and determine how they provide protection in the lung against influenza. We will ask if ThCTL and Thi7 give rise to committed memory subsets and determine their roles in combatting influenza. To accomplish these aims we will: 1) Isolate defined CD4 effector subsets generated in vitro and develop a scheme to separate them when they develop in vivo. We will define their cytokine and chemokine profiles, their migration and their involvement in help, cytotoxicity and protection against challenge with influenza. We will use the functional profile to develop a "signature" for each subset; 2) We will determine each subset's ability to give rise to memory cells that respond to challenge and develop into secondary effectors and ask if they retain the same functional potential as they progressively differentiate; and 3) We will evaluate the mechanisms used by each memory Th subset to provide protection against lethal flu challenge. We will collaborate with: 1) Project 2 to determine which how the CD4 subsets compare with parallel CDS effector and memory subsets; 2) Project 3 to determine migrafion of the CD4 subsets, and behavior in the lung and how interactions with selectins regulates function and memory generation from effectors; 3) Project 4 to investigate whether similar TuberculosisAg-speeific CD4 subsets can improve protecfion against Tuberculosis infecfion. RELEVANCE (See instructions): Current vaccines for influenza are based on induction of Ab specific for coat proteins that change each year, so they provide only short term protecfion. Knowing the mechanisms by which memory T cells provide immunity, should suggest new CD4 T cell correlates of protection and provide insights that can be used to develop new strategies for improved vaccines, which could be targeted towards inducing robust T cell memory, in addition to antibody, so that immunization will be more effective and longlasting.