Mucosal T Cell Memory to Pathogens

描述（由申请人提供）：粘膜组织代表最常见的感染部位。通过接种疫苗在粘膜部位建立记忆性CD8 T细胞可能对保护宿主免受某些感染（包括HIV）至关重要。然而，令人惊讶的是，关于胃肠道和生殖器粘膜内记忆性CD8 T细胞的特性，调节其建立、维持和分化状态的机制，以及最重要的是，这些组织内的粘膜记忆性CD8 T细胞实际上对局部感染的保护作用知之甚少。这些知识上的差距是成功开发针对粘膜病原体的保护性CD8 T细胞疫苗的主要障碍。本提案的主要目标是使用小鼠感染模型来确定保护性CD8 T细胞免疫是如何在粘膜表面调节的。为了解决这个问题，我们将：1)定义调节位置特异性粘膜记忆CD8 T细胞分化状态的机制，2)确定控制粘膜组织内CD8 T细胞迁移和维持的过程，以及3)测试记忆CD8 T细胞定位和分化状态与宿主保护自身免受粘膜表面细胞内病原体侵袭的能力之间的关系。具体来说，我们将验证在粘膜感染入口建立保护性CD8 T细胞免疫的假设是由三个过程控制的：淋巴组织内启动时的发育线索，粘膜实质内抗原特异性T细胞捕获的调节，以及在不同粘膜组织中不同的定位特异性线索和控制记忆T细胞分化程序。我们的研究可能为设计疫苗提供信息，这些疫苗可以在感染的粘膜入口处最佳地建立保护性CD8 T细胞免疫。

DESCRIPTION (provided by applicant): Mucosal tissues represent the most common sites of infection. Establishing memory CD8 T cells at mucosal sites through vaccination may be critical for protecting the host against certain infections, including HIV. However, surprisingly little is known about the properties of memory CD8 T cells within the gastrointestinal and genital mucosa, the mechanisms that regulate their establishment, maintenance and differentiation state, and most importantly, what mucosal memory CD8 T cells within these tissues actually contribute to protection from local infections. These gaps in knowledge represent a major barrier to the successful development of protective CD8 T cell vaccines against mucosal pathogens. The main goal of this proposal is to use mouse models of infection to determine how protective CD8 T cell immunity is regulated at mucosal surfaces. To address this question, we will: 1) define mechanisms that regulate location-specific mucosal memory CD8 T cell differentiation states, 2) determine processes that govern CD8 T cell migration and maintenance within mucosal tissues, and 3) test the relationship between memory CD8 T cell location and differentiation state and the ability of the host to protect itself against intracellular pathogens encountered at mucosal surfaces. Specifically, we will test the hypothesis that establishing protective CD8 T cell immunity at mucosal portals of infection is controlled by three processes: developmental cues during priming within lymphoid tissues, the regulation of antigen-specific T cell trapping within mucosal parenchyma, and location specific cues that vary among different mucosal tissues and control memory T cell differentiation programs. Our studies may provide information for the design of vaccines that optimally establish protective CD8 T cell immunity at mucosal portals of infection. PUBLIC HEALTH RELEVANCE: Mucosal tissues represent the most common site of infections. These studies will examine how the establishment, maintenance, and differentiation of memory CD8 T cells is regulated within mucosal tissues, and will test the ability of mucosal memory CD8 T cells to protect the host upon local exposure to intracellular pathogens. Achieving these aims will benefit the design of CD8 T cell vaccines.