Defining a memory checkpoint for CD4 T cells

描述（由申请方提供）：活病原体感染产生令人印象深刻的T细胞效应子应答，其清除病毒并导致产生记忆性CD 4和CD 8 T细胞以及产生病原体抗体的长寿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，但最强大的免疫力发生在所有成分都存在的时候。疫苗诱导的免疫记忆也可以成为对抗传染病的有力工具。尽管B细胞免疫可容易地被呈现被B细胞识别的快速变化的表面蛋白的病毒和其它病原体阻碍，但大多数注意力集中在诱导中和抗体，而很少注意实现T细胞免疫。目前的许多疫苗在激发CD 4 T细胞免疫方面做得很差，因此效果不如预期。我们已经分析了CD 4效应器，是非常容易凋亡死亡成为休息，长寿的记忆CD 4 T细胞的过程。我们发现，在甲型流感病毒感染后，CD 4记忆细胞的产生依赖于效应子在应答高峰时识别病原体。效应子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批效应物的短期和长期存活，因此它们可以过渡到记忆并维持数月或数年。没有这些组件，很少或没有CD 4记忆发展。因此，该步骤充当“内存检查点”。我们认为，大多数记忆性CD 4 T细胞需要这些事件才能成为记忆，病原体不仅提供了CD 4 T细胞必须识别的抗原，而且还提供了“危险信号”，以直接激活CD 4 T细胞以有效方式相互作用的细胞。我们还提出，CD 4 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，驱动向记忆的过渡，与进一步的效应分化形成对比。我们将测试这些假设，并定义所涉及的机制途径。通过这样做，我们希望发现CD 4记忆产生的关键要求，这将为开发更有效的疫苗以实现CD 4记忆提供信息。

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.