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.

CD_4记忆子集的产生和持久性 最近，我们发现流感特异性的CD4T细胞效应器通过 直接细胞杀伤活性(ThCTL)和对抗体的帮助，这表明额外的功能异质性 在可能导致CD4记忆异质性并帮助我们发现新的 疫苗诱导保护的机制。我们最近有证据表明，产生IL-17的CD4也在 在抗击流感方面的作用。我们在这里的目标是评估Thct细胞代表一个独特的 与Thi和Thi7一起参与有效免疫反应的功能专门化亚群。我们会 在效应器阶段将ThCTL与Thi7和Thi亚集进行比较，以进一步定义它们各自的功能 并确定它们如何在肺部提供抵御流感的保护。我们将询问Thctl和Thi7是否给予 上升到承诺的记忆亚集，并确定它们在抗击流感中的作用。 为了实现这些目标，我们将：1)分离在体外产生的明确的CD4效应亚群，并开发一种 当它们在体内发育时，计划将它们分离。我们将定义它们的细胞因子和趋化因子图谱， 它们的迁徙和参与帮助、细胞毒性和抵御流感挑战的保护。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响应挑战和发育的记忆细胞的能力 转化为次级效应器，并询问它们是否保持了与它们逐渐 区分；以及3)我们将评估每个内存Th子集提供保护所使用的机制 对抗致命的流感挑战。 我们将与以下项目合作：1)项目2，以确定哪些CD4子集与并行CDS相比如何 效应器和记忆亚集；2)项目3，以确定CD4亚集的偏头痛，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生成；3)项目 4.研究类似的结核抗原特异性CD4亚群是否能提高对 肺结核感染。 相关性(请参阅说明)： 目前的流感疫苗是基于诱导针对外壳蛋白的特异性抗体，这种抗体每年都会改变， 因此，它们只能提供短期保护。了解记忆T细胞提供 免疫力，应该提出新的CD4T细胞保护相关因素，并提供可用于 开发改进疫苗的新策略，目标可能是诱导强大的T细胞 记忆，除了抗体，让免疫会更有效、更持久。