Memory CD8 T Cell Responses After Multiple Antigen Encounters

描述（由申请人提供）：在感染或免疫后形成和维持记忆性CD 8 T细胞群的能力是适应性免疫应答的标志，也是针对感染性疾病或癌症免疫治疗的保护性疫苗接种的一个基础。由于对感染的保护水平与病原体暴露时存在的记忆性CD 8 T细胞的数量成比例，因此目前使用的许多疫苗涉及初始免疫，随后是一次或多次加强免疫（“初免-加强”方案）。类似地，仅接受单次免疫接种的个体在遇到病原体时可能会接受二次刺激，并且即使在没有接种疫苗的情况下，个体也可能暴露于同一病原体的多轮感染。因此，需要了解在多次抗原暴露后产生的CD 8 T细胞应答。重要的是，记忆性CD 8 T细胞的大多数研究都集中在对初次感染或疫苗接种的应答上。这是一个关键的知识差距，因为尚不清楚Ag暴露的数量如何影响CD 8 T细胞群的特征及其抵御感染的能力。我们的长期目标是充分了解多种抗原相遇对CD 8 T细胞群的功能性影响。这些信息对于理解如何最好地产生和操纵疫苗接种所获得的保护性免疫将是重要的。我们将测试的中心假设，抗原刺激的数量将决定重要的表型和功能特性的记忆CD 8 T细胞群。基于我们在小鼠感染模型和CD 8 T细胞免疫方面的专业知识，以及强有力的初步数据指导，我们已做好充分准备开展这些研究。我们已经开发了新的方法，这将使全面和详细的分析CD 8 T细胞群体响应多种抗原的遭遇。因此，我们提出了以下具体目标：SA 1-确定抗原接触的数量如何控制CD 8 T细胞的寿命。SA 2-评价记忆性CD 8 T细胞群对多种抗原刺激的反应的表型和功能差异。SA 3-定义炎症在产生二级（2 o）和三级（3 o）记忆CD 8 T细胞应答中的作用。公共卫生相关性：大多数关于记忆性CD 8 T细胞的研究都集中在对原发性感染和/或疫苗接种的反应上。然而，加强免疫通常用于增加保护性CD 8 T细胞数量，并且是用于保护人类免受感染性疾病的疫苗的共同特征。该提案的目标是充分表征多轮Ag刺激对CD 8 T细胞群体施加的功能性后果，这对于理解如何最好地通过疫苗接种产生保护性免疫将具有重要意义。

DESCRIPTION (provided by applicant): The ability to develop and sustain populations of memory CD8 T cells after infection or immunization is a hallmark of the adaptive immune response and one basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the level of protection to infection is proportional to the number of memory CD8 T cells present at the time of pathogen exposure, many vaccines in use today involve an initial immunization that is followed by one or more booster ('prime-boost' protocols) immunizations. Similarly, individuals that receive only a single immunization may receive a secondary stimulation when they encounter the pathogen and, even in the absence of vaccination individuals might be exposed to multiple rounds of infection with the same pathogen. Therefore, there is a need to understand CD8 T cell responses generated after numerous antigen exposures. Importantly, most studies of memory CD8 T cells have focused on the response to primary (1o) infection or vaccination. This is a critical knowledge gap since it is not known how the number of Ag-exposures can influence the characteristics of CD8 T cell populations and their ability to defend against infection. Our long term goal is to fully understand the functional consequences imposed on CD8 T cell populations by multiple antigen encounters. This information will be significant in understanding how best to generate and manipulate protective immunity achieved by vaccination. We will test the central hypothesis that the number of antigen-stimulations will dictate the important phenotypic and functional characteristics of memory CD8 T cell populations. We are well prepared to undertake these studies based upon our expertise in mouse models of infections and CD8 T cell immunity coupled with the guidance of strong preliminary data. We have developed novel methodologies that will enable comprehensive and detailed analyses of CD8 T cell populations responding to multiple antigen encounters. Thus, we propose the following Specific Aims: SA1 - Determine how the number of antigen encounters controls the longevity of CD8 T cells. SA2 - Evaluate the phenotypic and functional differences between memory CD8 T cell populations in response to multiple antigen-stimulations. SA3 - Define the role of inflammation in generation of secondary (2o) and tertiary (3o) memory CD8 T cell responses. Public Health Relevance: Most studies of memory CD8 T cells have focused on the response to primary (1o) infection and/or vaccination. However, booster immunizations are often used to increase protective CD8 T cell numbers and are common feature of vaccines used to protect humans against infectious disease. The goal of this proposal, to fully characterize the functional consequences imposed on CD8 T cell populations by multiple rounds of Ag-stimulations, will be significant in understanding how best to generate protective immunity by vaccination.