Mechanisms of Listeria-Specific Immunity

描述（由申请人提供）：该项目的目标是确定对单核增生李斯特菌的免疫反应是如何通过抗原呈递细胞的激活来调节的。李斯特菌通过模式识别受体和信号转接器网络触发APC激活。在进入细胞质时转导的信号是细菌的毒力和保护性免疫发展所必需的。同样，通过toll样受体适配器MyD88的信号传导对于李斯特菌感染诱导的DC成熟反应的重要部分是必不可少的。我们已经确定了许多关键分子诱导DC由李斯特细胞质进入。我们确定DC的共刺激分子和炎症细胞因子的表达依赖于溶血素、LLO和细菌细胞质入口的表达。我们还确定了这些分子在启动CD8+ T细胞增殖和功能中的作用。现在，我们将在Specific Aim 1中提出的研究中，通过检测toll样受体、TLR适配器和细胞质受体的作用，探索李斯特菌诱导DC成熟的分子基础。我们还将利用李斯特菌感染的DC作为体内免疫原，确定这些分子在产生对李斯特菌的保护性免疫中的作用。然后我们将确定由李斯特菌感染诱导的共刺激分子和细胞因子在免疫突触形成中的作用，具体目标2中提出的研究。这些新的研究将揭示T细胞如何与受感染的抗原呈递细胞相互作用产生保护性T细胞反应。我们的研究将为这种细胞内细菌与宿主免疫系统的相互作用提供重要的见解，并将有助于设计针对这种病原体的有效疫苗。

DESCRIPTION (provided by applicant): The goal of this project is to determine how the immune response to Listeria monocytogenes is regulated by activation of antigen presenting cells. Listeria trigger APC activation through a network of pattern recognition receptors and signaling adapters. Signals transduced upon cytoplasmic entry are required for virulence of the bacteria and for development of protective immunity. Likewise, signaling through the Toll-like receptor adapter MyD88 is essential for a significant portion of the DC maturation response induced by listerial infection. We have identified many of the key molecules induced in DC by listerial cytoplasmic entry. We determined that the expression of costimulatory molecules and inflammatory cytokines by DC was dependent upon expression of the hemolysin, LLO and bacterial cytoplasmic entry. We have also determined the role of each of these molecules in priming CD8+ T cell proliferation and function. We will now explore the molecular basis for DC maturation induced by Listeria by examining the role of Toll-like receptors, TLR adapters, and cytosolic receptors with the studies proposed in Specific Aim 1. We will also determine the role of these molecules in generating protective immunity to Listeria using Listeria-infected DC as an immunogen in vivo. We will then determine the role of costimulatory molecules and cytokines induced by listerial infection in the formation of the immunological synapse with the studies proposed in specific aim 2. These novel studies will reveal how the interaction of T cells with infected antigen presenting cells gives rise to protective T cell responses. Our studies will provide important insights into the interaction of this intracellular bacteria with the host immune system and will aid the design of efficacious vaccines against this pathogen.