T Cell Response to Listeria Monocytogenes Infection

摘要 诱导对细菌感染的保护性免疫反应的关键因素 是不完全理解的。在单核细胞增多性李斯特氏菌感染的情况下， B类优势病原体CD8T细胞在影响不育性免疫中起重要作用。 LM在多个层面上与疫苗学以及生物防御计划进行对接 对于LM作为候选疫苗的巨大潜力，也作为一种疫苗制剂 故意污染和产生高毒力的重组菌株。我们的工作 已经开始检查有效免疫所需的参数，以杀死或 突变型LM作为潜在的疫苗载体。具体地说，热免疫可杀死LM (HKL)或辐照LM(IRL)诱导的不同T细胞激活模式的特征 通过更强大的CD8T细胞记忆诱导后接种IRL。 然而，IRL免疫并没有诱导T细胞的激活和记忆水平 用活的LM感染获得的诱导。因此，这是一个很好的划定系统 促进不同程度CD8 T细胞活化的机制 由同一病原体的不同形式产生的。根据我们的初步数据， 新提出的研究集中在整合有效的CD8 T细胞免疫的解剖 共刺激和遗传作用下的反应启动和记忆T细胞再激活 驱动保护性免疫反应所需的程序。假设 活感染诱导的应答与减毒疫苗免疫的份额 生成保护性记忆的常见基本组件将分三个阶段进行测试 目标： 具体目的1.确定共刺激和CD4T细胞在 在LM感染或接种疫苗后的启动和保护性召回反应。 特定目的2.确定有效CD8 T细胞的解剖学特征 疫苗接种和召回反应。 特定目的3.明确CD8应答T细胞的遗传特征 对有效接种疫苗的反应。

ABSTRACT The factors essential to induction of a protective immune response to bacterial infections are incompletely understood. In the case of Listeria monocytogenes (LM) infection, a category B Priority Pathogen, CD8 T cells are important in effecting sterilizing immunity. LM interfaces at multiple levels with vaccinology as well as the Biodefense initiative due to the significant potential of LM as a vaccine candidate but also as an agent for intentional contamination and generation of highly virulent recombinant strains. Our work has begun to examine the parameters required for effective immunization with killed or mutant LM as potential vaccine vehicles. Specifically, immunization with heat killed LM (HKL) or irradiated LM (IRL) induced distinct patterns of T cell activation characterized by much more robust CD8 T cell memory induction following vaccination with IRL. However, IRL immunization did not induce the level of T cell activation and memory induction obtained with live LM infection. Thus, this is an excellent system for delineation of the mechanisms involved in promotion of distinct degrees of CD8 T cell activation generated by distinct forms of the same pathogen. Based on our preliminary data, the newly proposed studies focus on integrating the anatomy of effective CD8 T cell immune response initiation and memory T cell reactivation with the costimulatory and genetic programming necessary to drive a protective immune response. The hypothesis that responses induced by live infection versus immunization with attenuated vaccines share common essential components to generate protective memory will be tested in three aims: Specific Aim 1. To determine the role of costimulation and CD4 T cell help in priming and protective recall responses following LM infection or vaccination. Specific Aim 2. To determine the anatomical features of effective CD8 T cell vaccination and recall responses. Specific Aim 3. To define the genetic signature of responding CD8 T cells in response to effective vaccination.