Visualizing, Quantifying, and Modeling of T Cell Response to Listeria Infection

单核细胞增多性李斯特菌是一种细胞内细菌病原体，可引起严重感染 免疫抑制的宿主。在正常宿主中，单核细胞增多性李斯特菌被强大的T细胞反应清除 包括CDS和CD4人群。CD4T细胞在肉芽肿细菌分离中的作用 并通过巨噬细胞激活而杀伤，而CD8 T细胞产生细胞毒性T淋巴细胞， 直接杀死受感染的宿主细胞。单纯的单核细胞增多性李斯特氏菌特异性T细胞的启动仅限于第一次 感染几天，一旦产生活跃的CTL就结束，导致假设CTL介导 抗原提呈树突状细胞的杀伤阻止了初始T细胞的进一步启动。双光子激光器 扫描显微镜生成了T细胞在淋巴结中迁移的生动图像，并提供了对 有抗原的树突状细胞如何与稀有抗原特异性的初始T细胞接触。随机性 全套扫描假说认为，原始T细胞通过T细胞区快速随机迁移 包含延伸长树突状的DC网络，使得每个树突状细胞接触5000个T细胞 小时。基于玻璃形成液理论模型的模拟表明，最优搜索 初始T细胞与抗原阳性DC相互作用的策略是与 最优的吸引范围取决于感染ARC的数量。我们将使用来自 更好地了解幼稚T细胞在体内和体内寻找抗原阳性APC的理论和实验 在宿主中控制或传播感染的后果。在目标1中，我们将使用计算 确定最优和实际搜索策略的方法和实验 CD4和CDS反应的不同阶段。在目标2中，我们将测试树突状细胞在T细胞启动和 确定树突状细胞数量的减少如何改变CD4和CDS T细胞的激活和信号 体内整合。在目标3中，我们将开发单核细胞增多性李斯特氏菌在生物体中的生长模型和 通过CD4和CDS T细胞反应进行控制，并进行实验以补充已发表的关于 感染的自然病史。这一结果将为获得性免疫提供定量的见解。 对单核细胞增多性李斯特菌的反应，可能导致改进疫苗接种策略和范例。

Listeria monocytogenes is an intracellular bacterial pathogen that causes severe infections in immunosuppressed hosts. In normal hosts L. monocytogenes is cleared by a robust T cell response including both CDS and CD4 populations. CD4 T cells contribute to isolation of the bacteria in granulomas and killing through macrophage activation, whereas CD8 T cells give rise to cytotoxic T lymphocytes that directly kill infected host cells. The priming of naive L. monocytogenes specific T cells is limited to the first few days of infection and ends once active CTL are produced, leading to the hypothesis that CTL mediated killing of antigen presenting dendritic cell prevents further priming of naive T cells. Two photon laser scanning microscopy has generated vivid images of T cell migration in lymph nodes and provided insight into how dendriic cells with antigen come into contact with rare antigen specific naive T cells. The stochastic repertoire scanning hypothesis states that naive T cells migrate rapidly and randomly in through T cell zones containing networks of DC extending long dendrites such that each dendritic cell contacts 5000 T cells per hour. Simulations based on theoretical models of glass forming liquids suggest that the optimal search strategy for naive T cells interaction with antigen positive DC is to have short range attractions with the optimal range of attraction dependent upon the number of infected ARC. We will use simulations from theory and experiments to better understand the search of naive T cells for antigen positive APC in vivo and the consequences of the containment or spread of infection in the host. In Aim 1 we will use computations methods and experimentation to determine the optimal and actual search strategy at the priming and effector phases of the CD4 and CDS responses. In Aim 2 we will test the role of dendritic cells in T cell priming and determine how reduction in dendritic cell numbers alters CD4 and CDS T cell activation and signal integration in vivo. In Aim 3 we will develop models for L. monocytogenes growth in the organism and control by CD4 and CDS T cell responses and perform experiments to complement published data on the natural history of the infection. The results will provide quantitative insights into the adaptive immune response to L. monocytogenes that may lead to improved vaccination strategies and paradigms.