T Cell Response to Listeria Monocytogenes Infection

描述(由申请人提供)：诱导对细菌感染的保护性免疫反应所必需的因素尚未完全了解。单核细胞增多性李斯特菌是B类优势致病菌，CD8T细胞在杀菌免疫中起重要作用。由于LM作为候选疫苗的巨大潜力，以及作为故意污染和产生高毒力重组菌株的试剂，LM在多个层面上与疫苗学和生物防御倡议相结合。我们的工作已经开始检查以灭活或突变的LM作为潜在疫苗载体进行有效免疫所需的参数。具体地说，热灭活LM(HKL)或辐照LM(IRL)免疫诱导了不同的T细胞激活模式，其特征是在接种IRL后更强劲地诱导了CD8T细胞的记忆。然而，IRL免疫不能诱导活体LM感染所获得的T细胞活化和记忆诱导。因此，这是一个很好的系统，用于描述同一病原体的不同形式产生的不同程度的CD8 T细胞激活所涉及的促进机制。基于我们的初步数据，新提出的研究重点是将有效的CD8 T细胞免疫反应启动和记忆T细胞重新激活的解剖与驱动保护性免疫反应所需的共刺激和遗传编程相结合。假设活体感染和减毒疫苗免疫诱导的反应具有共同的基本成分，以产生保护性记忆，这一假设将在三个目标进行检验：1.确定共刺激和CD4T细胞帮助在LM感染或疫苗接种后的启动和保护性回忆反应中的作用。具体目的2.确定有效的CD8T细胞疫苗接种的解剖学特征和召回反应。具体目的3.明确免疫应答CD8T细胞的遗传特征。与公共卫生相关：这项提案的目标是确定某些疫苗比其他疫苗更有效的原因。通过研究不同形式的细菌疫苗，我们的研究将帮助我们设计出更有效的疫苗接种策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine the reasons why some vaccines are more effective than others. By studying different forms of a bacterial vaccine, our studies will help us devise more effective vaccination strategies.