Defining a memory checkpoint for CD4 T cells

定义 CD4 T 细胞的记忆检查点

• 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
• 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

 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(申请人提供)：感染活的病原体会产生令人印象深刻的T细胞效应反应，这种反应可以清除病毒，并导致产生记忆的CD4和CD8T细胞以及产生抗病原体抗体的长寿B细胞。免疫反应的每一个手臂都可以提供有效的保护，防止再次感染，但最强大的免疫力发生在所有组件都存在的情况下。疫苗诱导的免疫记忆也可以成为对抗传染病的有力工具。大多数人的注意力集中在诱导中和抗体上，而对获得T细胞免疫的关注要少得多，尽管B细胞免疫很容易被病毒和其他病原体挫败，这些病毒和其他病原体呈现出快速变化的B细胞识别的表面蛋白。许多目前的疫苗在激发CD4T细胞免疫方面做得很差，因此效果不如它们应有的效果。我们已经分析了高度易受凋亡死亡影响的CD4效应器成为静止的、长期记忆的CD4T细胞的过程。我们发现，在甲型流感病毒感染后，CD4记忆细胞的产生依赖于在反应高峰期识别病原体的效应器。效应器必须产生生长和生存细胞因子IL-2。这种对病原体的识别导致了一小群效应者的短期和长期存活，这样他们就可以过渡到记忆中，并维持数月或数年。如果没有这些成分，很少或根本没有CD4记忆的形成。因此，此步骤相当于一个“内存检查点”。我们认为，大多数记忆的CD4T细胞需要这些事件才能成为记忆，病原体不仅提供CD4T细胞必须识别的抗原，而且还提供“危险信号”，以有效地直接激活与CD4T细胞相互作用的细胞。我们还提出，CD4T细胞与病原体激活的抗原提呈细胞的相互作用提供了独特的信号，推动了与进一步的效应器分化相反的向记忆的转变。我们将测试这些假设，并定义所涉及的机制路径。在这样做的过程中，我们希望发现产生CD4记忆的关键要求，这将有助于开发更有效的疫苗来实现CD4记忆。