Generation and persistence of CD4 memory subsets

CD4 内存子集的生成和持久化

• 批准号: 8316250
• 负责人: SUSAN L SWAIN
• 金额: $ 37.76万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316250
• 关键词: Antibodies; Antigens; Autoimmunity; B-Lymphocytes; Behavior; CD4 Positive T Lymphocytes; Capsid Proteins; Cells; Commit; Communicable Diseases; Dose; Exposure to; Generations; Goals; Heterogeneity; Immune response; Immunity; Immunization; In Vitro; Infection; Influenza; Instruction; Interleukin-10; Interleukin-17; Learning; Lung; Memory; Play; Production; Regulatory T-Lymphocyte; Role; Scheme; Selectins; Staging; Structure of germinal center of lymph node; T memory cell; Tuberculosis; Vaccines; base; chemokine; combat; cytokine; cytotoxicity; flu; improved; in vivo; influenza virus vaccine; insight; migration; pathogen; response

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.

CD4内存子集的产生和持久性 最近，我们发现特定于流感的CD4 T细胞效应器可通过美德保护致命挑战 直接细胞溶解活性（THCTL）和AB的帮助，提出了其他功能异质性 在可能有助于CD4内存异质性并帮助我们发现新的CD4子集中 疫苗诱导的保护机制。我们最近有证据表明，IL-17产生CD4也播放 在对抗流感中的作用。我们的目标是评估Thctl细胞代表独特的假设 在功能专业的子集中，THI和THI7参与了有效的免疫反应。我们将 将THCTL与Thi7和Thi子集进行比较，以进一步定义其各自的功能 并确定它们如何在肺中提供防止流感的保护。我们会问THCTL和THI7是否给予 升至承诺的记忆子集并确定它们在对抗流感中的作用。 为了实现这些目标，我们将：1）隔离定义的CD4效应子集在体外生成并发展 在体内发展时将它们分开的计划。我们将定义它们的细胞因子和趋化因子谱， 他们的迁移以及参与帮助，细胞毒性和保护流感挑战的迁移。我们 将使用功能配置文件为每个子集开发一个“签名”； 2）我们将确定每个子集产生对挑战和发展做出反应的记忆单元的能力 进入次级效应子，并询问它们是否保留与逐渐相同的功能潜力 区分; 3）我们将评估每个内存使用的机制以提供保护 反对致命的流感挑战。 我们将与：1）项目2合作，以确定CD4子集与并行CD的比较的方式 效应子和内存子集； 2）项目3确定CD4子集的迁移以及行为 肺以及与选择素的相互作用如何调节效应子的功能和内存的产生； 3）项目 4研究类似的结核病杂质CD4子集是否可以改善针对 结核病的不适。 相关性（请参阅说明）： 当前的流感疫苗基于每年改变的外套蛋白的诱导诱导， 因此，它们仅提供短期protecfion。知道记忆T细胞提供的机制 免疫力应提示保护的新CD4 T细胞相关性，并提供可用于的见解 制定改进疫苗的新策略，可以针对诱导强大的T细胞 除了抗体之外，记忆将更有效，更持久。