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

单核细胞增生李斯特菌是一种细胞内细菌病原体，可导致严重感染， 免疫抑制宿主。在正常寄主L.单核细胞增多症是由强大的T细胞反应清除 包括CD 8和CD 4群体。CD 4 T细胞有助于肉芽肿中细菌的分离 并通过巨噬细胞活化进行杀伤，而CD 8 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。naive L.单核细胞增多症特异性T细胞仅限于第一个 几天的感染和结束时，活性CTL产生，导致假设，CTL介导的 杀死抗原呈递树突细胞防止了初始T细胞的进一步引发。双光子激光器 扫描显微镜已经生成了淋巴结中T细胞迁移的生动图像，并提供了对 具有抗原的树突细胞如何与罕见的抗原特异性初始T细胞接触。随机 库扫描假说指出，初始T细胞快速和随机地迁移通过T细胞区 含有DC延伸长树突的网络，使得每个树突细胞接触5000个T细胞/ 小时基于玻璃形成液体的理论模型的模拟表明， 幼稚T细胞与抗原阳性DC相互作用的策略是与抗原阳性DC具有短程吸引力。 最佳吸引范围取决于感染ARC的数量。我们将使用模拟从 理论和实验，以更好地理解体内抗原阳性APC的初始T细胞的搜索， 感染在宿主中的遏制或传播的后果。在目标1中，我们将使用计算 方法和实验，以确定最佳和实际的搜索策略，在启动和效应 CD 4和CDS反应的阶段。在目标2中，我们将测试树突状细胞在T细胞引发中的作用， 确定树突状细胞数量的减少如何改变CD 4和CDS T细胞的活化和信号传导 体内整合。在目标3中，我们将为L开发模型。单核细胞增多症的生长， 通过CD 4和CD 8 T细胞反应进行控制，并进行实验以补充已发表的关于 感染的自然史。这些结果将为适应性免疫提供定量的见解。 回应L。单核细胞增多症，可能导致改进的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.