Defining a memory checkpoint for CD4 T cells

定义 CD4 T 细胞的记忆检查点

基本信息

批准号：
8938979
负责人：
SUSAN L SWAIN
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8938979
关键词：
Antibodies Antigen-Presenting Cells Antigens Apoptosis Apoptotic Attention B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cells Cessation of life Communicable Diseases Dependence Development Dose Event Gene Expression Gene Expression Profiling Generations Genes Growth Human IL7R gene Immune response Immunity Immunologic Memory Inactivated Vaccines Infection Influenza Influenza A virus Interleukin-2 Interleukin-7 Life Location Lung Mediator of activation protein Membrane Proteins Memory Memory B-Lymphocyte Modeling Molecular Nature Occupations Pathway interactions Pattern Predisposition Process Production Property Rest Signal Pathway Signal Transduction Source Staging T-Lymphocyte Testing Time Up-Regulation Vaccination Vaccine Design Vaccines Viral Antigens Virus Virus Diseases arm autocrine cohort cytokine differential expression fighting insight memory CD4 T lymphocyte neutralizing antibody novel pathogen public health relevance response tool

项目摘要

DESCRIPTION (provided by applicant): Infection with a live pathogen generates an impressive T cell effector response that that clears virus and results in generation of memory CD4 and CD8 T cells as well long-lived B cells that make antibody to pathogen. Each of these arms of the immune response can provide potent protection against re-infection, but the most powerful immunity occurs when all components are present. Vaccine-induced immunological memory can also be a powerful tool to fight infectious diseases. Most attention has focused on inducing neutralizing antibody with much less attention given to achieving T cell immunity, even though B cell immunity can be readily thwarted by viruses and other pathogens that present rapidly changing surface proteins recognized by B cells. Many current vaccines do a poor job of eliciting CD4 T cell immunity and thus are less effective than they could be. We have analyzed the process in which CD4 effectors that are highly susceptible to apoptotic death become resting, long-lived memory CD4 T cells. We find that after influenza A virus infection, generation of CD4 memory cells is dependent on effectors recognizing the pathogen at the peak of the response. The effectors must produce the growth and survival cytokine, IL-2. This recognition of the pathogen leads to short and long- term survival of a small cohort of effectors so they can transition to memory and be maintained for months or years. Without these components little or no CD4 memory develops. Thus this step acts as a "Memory Checkpoint". We propose that most memory CD4 T cells require these events to become memory and that the pathogen provides not only the antigen the CD4 T cells must recognize, but also supplies "danger signals" to directly activates the cells that the CD4 T cells interact with in an effective way. We also propose that the interaction of CD4 T cells with pathogen-activated antigen-presenting cells provides unique signals that drive the transition to memory that contrasts to further effector differentiation. We will test these hypotheses and define the mechanistic pathways involved. In so doing we expect to discover key requirements for CD4 memory generation that will inform development of more effective vaccines to achieve CD4 memory.

描述（由申请人提供）：活病原体感染会产生令人印象深刻的 T 细胞效应反应，清除病毒并导致产生记忆 CD4 和 CD8 T 细胞以及长寿命 B 细胞，从而产生针对病原体的抗体。免疫反应的增强可以提供有效的保护，防止再次感染，但当所有成分都存在时，就会产生最强大的免疫力。疫苗诱导的免疫记忆也可以成为对抗传染病的有力工具。中和抗体很少关注实现 T 细胞免疫，尽管 B 细胞免疫很容易被病毒和其他病原体所阻碍，这些病原体呈现 B 细胞识别的快速变化的表面蛋白，许多当前的疫苗在引发 CD4 T 细胞方面效果不佳。我们分析了高度易受细胞凋亡影响的 CD4 效应细胞变成静息、长寿命记忆 CD4 T 细胞的过程，我们发现在甲型流感病毒感染后，CD4 的产生。记忆细胞依赖于效应器在反应高峰时识别病原体，效应器必须产生生长和存活细胞因子 IL-2，这种对病原体的识别导致一小群效应器的短期和长期存活。没有这些成分，CD4 很少或不会形成记忆，因此我们认为大多数记忆 CD4 T 细胞需要这些事件才能成为记忆。不仅提供抗原 CD4 T细胞必须识别，但也提供“危险信号”，以有效的方式直接激活 CD4 T 细胞与之相互作用的细胞。我们还提出，CD4 T 细胞与病原体激活的抗原呈递细胞的相互作用提供了独特的信号。驱动向记忆的转变，这与进一步的效应器分化形成鲜明对比。我们将测试这些假设并定义所涉及的机制途径，在此过程中，我们期望发现 CD4 记忆生成的关键要求，这将为开发更有效的疫苗来实现 CD4 记忆提供信息。