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

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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.