Molecular regulation and functional efficacy of T cell responses in a mouse model of social stress and patients with post-traumatic stress disorder (PTSD)

在这个项目中，我们将研究社会压力如何影响小鼠对病毒感染的免疫反应以及人类对树突状细胞（DC）免疫的免疫反应。我们将使用急性和慢性感染的小鼠与淋巴细胞性脉络丛脑膜炎病毒（LCMV）作为一个模型，以监测的特异性和功能的病毒特异性T细胞反应的压力的影响。社会压力将由居民-入侵者范式产生，这已被证明在被击败的小鼠中诱导明显的神经内分泌应激反应。将对细胞毒性T淋巴细胞和T辅助细胞进行表型和功能表征，监测其表位特异性，并测定病毒滴度。此外，在抗病毒免疫应答期间，将在应激和非应激小鼠中评估蛋白酶体的功能和组成以及树突状细胞的功能和迁移。我们将通过使用药理学激动剂和拮抗剂以及敲除小鼠来确定观察到的效应是否依赖于应激激素如糖皮质激素、肾上腺素或去甲肾上腺素。除了在小鼠中进行的实验之外，我们还将在健康的人类志愿者中进行实验，这些志愿者正在经历密集的考试阶段（14天内进行4次重要的主要考试）。与用标准化量表分析志愿者的心理应激反应平行，将如我们先前所进行的那样产生单核细胞衍生的DC，并用流感病毒基质表位Ml脉冲。将对检查阶段的志愿者和对照组进行皮内接种，并通过ELISPOT、增殖测定和MHC四聚体染色来确定对MI表位的CTL应答。将尝试将应激因素与免疫学数据相关联。

In this project we will investigate how social stress affects the immune response to a viral infection in the mouse and to dendritic cell (DC)-based immunization in the human. We will use the acute and chronic infection of the mouse with the lymphocytic choriomeningitis virus (LCMV) as a model to monitor the effects of stress on the specificity and function of the virus-specific T cell response. Social stress will be generated by the resident-intruder paradigm which has been shown to induce a pronounced neuroendocrine stress response in the defeated mice. The cytotoxic T lymphocytes and T helper cells will be phenotypically and functionally characterized, their epitope specificity will be monitored, and the virus titers will be determined. Moreover, the function and composition of proteasomes as well as the function and migration of dendritic cells will be assessed in stressed and unstressed mice during the antiviral immune response. We will determine if observed effects depend on stress hormones like glucocorticoids, epinephrine, or norepinephrine by using pharmacological agonists and antagonists as well as knock out mice. In addition to the experiments in mice we will conduct an experiment on healthy human volunteers who are going through an intensive phase of exams (4 important major exams within 14 days). In parallel to the analyses of psychological stress response of the volunteers with standardized scales, monocyte-derived DC will be generated as we have performed previously, and pulsed with the influenza virus matrix epitope Ml. Volunteers in the exam phase and a control group will be vaccinated intradermally and the CTL response to the MI epitope will be determined by ELISPOT, proliferation assay, and MHC tetramer staining. A correlation of stress factors with the immunological data will be attempted.