Memory CD8 T Cell Responses After Multiple Antigen Encounters

描述(由申请人提供)：在感染或免疫后发展和维持记忆CD8 T细胞群体的能力是适应性免疫反应的标志，也是预防传染病或癌症免疫治疗的保护性疫苗的基础之一。由于对感染的保护水平与病原体暴露时存在的记忆CD8 T细胞的数量成正比，目前使用的许多疫苗都包括初始免疫，然后是一次或多次加强免疫(‘Prime-Boost’方案)。同样，只接受一次免疫的个人在遇到病原体时可能会受到二次刺激，即使在没有接种疫苗的情况下，个人也可能接触到同一病原体的多轮感染。因此，有必要了解在多次抗原暴露后产生的CD8T细胞反应。重要的是，大多数对记忆CD8 T细胞的研究都集中在对初次感染或疫苗接种的反应上。这是一个关键的知识缺口，因为尚不清楚暴露于Ag的数量如何影响CD8T细胞群体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重抗原相遇对CD8T细胞群造成的功能后果。这些信息将对理解如何最好地产生和操纵通过接种疫苗实现的保护性免疫具有重要意义。我们将检验核心假设，即抗原刺激的数量将决定记忆CD8T细胞群体的重要表型和功能特征。基于我们在小鼠感染模型和CD8 T细胞免疫方面的专业知识，加上强大的初步数据的指导，我们已经为开展这些研究做好了充分的准备。我们已经开发了新的方法，可以全面和详细地分析CD8T细胞群对多种抗原相遇的反应。因此，我们提出了以下具体目标：SA1-确定抗原相遇的数量如何控制CD8T细胞的寿命。SA2-评估记忆CD8 T细胞群对多种抗原刺激的表型和功能差异。SA3-定义炎症在产生二级(2o)和三级(3o)记忆性CD8T细胞反应中的作用。公共卫生相关性：大多数关于记忆CD8 T细胞的研究都集中在对初次(10)感染和/或疫苗接种的反应上。然而，加强免疫经常被用来增加具有保护性的CD8 T细胞数量，这是用于保护人类免受传染病感染的疫苗的共同特征。这项建议的目标是充分描述多轮抗原刺激对CD8T细胞群施加的功能后果，这将对理解如何最好地通过疫苗接种产生保护性免疫具有重要意义。

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.