Infection and CD8 T Cell Memory: Development, Maintenance and Plasticity

描述(由申请人提供)：免疫记忆是免疫的一个决定性特征，它使我们能够开发疫苗，其中一些具有对致病传染病提供终身免疫的能力。虽然中和抗体通常是疫苗接种策略的重点，但细胞介导的保护，主要是以细胞毒性CD8 T细胞的形式，在对抗许多感染方面也发挥着重要作用。CD8T细胞对于杀死受感染的细胞、防止病原体的传播、甚至杀死一些癌细胞至关重要。CD8T细胞的长期保护来自于记忆性CD8T细胞，它具有很高的增殖能力，可以自我更新，在二次感染时几乎立即反应。然而，记忆群体并不是均匀的，至少可以识别出两个子集，效应记忆细胞(TEM)和中央记忆细胞(Tcm)。中药具有增强自我更新和增殖的能力，而透射电子显微镜似乎具有增强的效应功能。然而，对于这些亚群是如何发展的，以及它们是否代表着不同的谱系，或者是否可以对环境信号做出反应，人们仍然缺乏了解。鉴于记忆细胞可以存活几十年，了解这些子集的功能贡献以及它们是如何维持的是很重要的。我们实验室以前的工作表明，炎症信号可以诱导转录因子T-bet，该转录因子通过促进形成记忆能力降低的短期效应细胞(SLECs)来调节效应CD8 T细胞成为记忆细胞的潜力。我们建议研究T-bet是否也通过环境中的炎症信号影响记忆亚集的不同状态。我们还将进一步研究T-bet如何诱导效应期细胞终末分化。了解CD8 T细胞如何获得或失去记忆特征，对于开发更有效的疫苗以预防传染病和潜在的癌症至关重要。我们计划通过以下目标来解决这些问题：具体目标1：确定在缺乏抗原的情况下，是否可以通过降低T-bet来调节SLEC的分化状态。具体目标2：确定透射电子显微镜和中医记忆CD8 T细胞亚群是否相互转换，以及这一过程是否需要T-BET。特异性目标3：确定T-bet的候选靶点转录因子Zeb是否参与调节CD8T细胞的终末分化。

DESCRIPTION (provided by applicant): Immunological memory is a defining characteristic of Immunity, one that has allowed us to develop vaccines, some with the power to provide life-long immunity to pathogenic infectious diseases. While neutralizing antibodies have often been the focus of vaccination strategies, cell mediated protection, mainly in the form of cytotoxic CD8 T cells, also plays an important role in fighting many infections. CD8 T cells are crucial for killing infected cells, preventing the spread of pathogens, and even killing some cancer cells. Long-term CD8 T cell protection comes from memory CD8 T cells, which have a high proliferative capacity, can self renew, and respond almost immediately upon a secondary infection. However, the memory population is not uniform and at least two subsets can be identified, effector memory cell (TEM) and central memory cells (TCM). TCM have and increased capacity to self renew and proliferate, while TEM seem to have enhanced effector functions. Yet there is still a poor understanding of how these subsets develop and whether they represent different lineages or can interconvert in response to environmental signals. Given that memory cells can survive for decades it's important to understand the functional contribution of these subsets and how they are maintained. Previous work from our lab has shown that inflammatory signals can induce the transcription factor T-bet which modulates the potential of an effector CD8 T cell to become a memory cell by prompting the formation of short lived effector cells (SLECs) with reduced potential to form memory. We propose to investigate whether T-bet also plays a role in influencing the differention state of memory subsets through inflammatory signals in their environment. We will also further investigate how T-bet induces effector stage cells to terminally diferentiate. Understanding how CD8 Tcells acquire, or lose, memory characteristics is crucial for the development of more efficacious vaccines to protect from infectious diseases and potentially cancer. We plan on addressing these questions through the following aims: Specific Aim 1; To determine whether the differentiation state of SLECs can be modulated by reducing T- bet, in the absence of antigen. Specific Aim 2: To determine if TEM and TCM memory CD8 T cell subsets interconvert and if T-bet is required for this process. Specific Aim 3: To determine if the transcription factor ZEB, a candidate target of T-bet, co-regulates the terminal differentiation of CD8 T cells.