Defining a memory checkpoint for CD4 T cells

定义 CD4 T 细胞的记忆检查点

• 批准号: 9064064
• 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
• 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/9064064
• 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; Health; 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; response; tool

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，可清除病毒并导致产生记忆 CD4 和 CD8 T 细胞以及产生病原体抗体的长寿命 B 细胞。免疫反应的每一个分支都可以提供有效的保护，防止再次感染，但只有当所有成分都存在时，才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。大多数注意力集中在诱导中和抗体上，而很少关注实现 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，这些病原体呈现出 B 细胞识别的快速变化的表面蛋白。目前许多疫苗在引发 CD4 T 细胞免疫方面效果不佳，因此效果不佳。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，甲型流感病毒感染后，CD4 记忆细胞的产生取决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，因此它们可以转变为记忆并维持数月或数年。如果没有这些组件，CD4 记忆就很少或根本不会发展。因此，此步骤充当“内存检查点”。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，并且病原体不仅提供CD4 T细胞必须识别的抗原，而且还提供“危险信号”以直接激活CD4 T细胞以有效方式相互作用的细胞。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。