T Cell Response to Listeria Monocytogenes Infection

描述（由申请方提供）：对诱导针对细菌感染的保护性免疫应答的关键因素尚未完全了解。在单核细胞增生李斯特菌（LM）感染的情况下，一种B类优先病原体，CD8 T细胞在影响杀菌免疫中是重要的。LM在多个层面上与疫苗学以及生物防御计划相结合，因为LM不仅具有作为候选疫苗的巨大潜力，而且还具有故意污染和产生高毒力重组菌株的潜力。我们的工作已经开始检查所需的参数与杀死或突变LM作为潜在的疫苗车辆有效免疫。具体地，用热灭活的LM（HKL）或辐照的LM（IRL）免疫诱导不同的T细胞活化模式，其特征在于用IRL接种后更稳健的CD8 T细胞记忆诱导。然而，IRL免疫没有诱导T细胞活化和记忆诱导的水平与活LM感染。因此，这是一个很好的系统，用于描绘的机制，参与促进不同程度的CD8 T细胞活化产生的不同形式的相同的病原体。基于我们的初步数据，新提出的研究重点是将有效的CD8 T细胞免疫应答启动和记忆T细胞再激活的解剖学与驱动保护性免疫应答所需的共刺激和遗传编程相结合。活感染与减毒疫苗免疫诱导的应答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中进行检验：具体目标1。确定共刺激和CD4 T细胞在LM感染或疫苗接种后启动和保护性回忆反应中的作用。具体目标2。确定有效的CD8 T细胞疫苗接种和回忆反应的解剖学特征。具体目标3。确定响应有效疫苗接种的响应性CD8 T细胞的遗传特征。公共卫生相关性：本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制定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.