The influence of chronic stress on T cell immunity

Abstract

Chronic environmental and psychological stress has long been suspected to increase the susceptibility and outcome of numerous infectious and inflammatory diseases. The release of neurotransmitters (catecholamines) and adrenal hormones (glucocorticoids) has been well documented as the basis for a connection between the central nervous system and peripheral components of the immune system. Glucocorticoids, the end products of stress-induced neuroendocrine pathways and the hypothalamic-pituitary-adrenal (HPA) axis, belong to the most potent anti-inflammatory hormones in the body and serve to control immune responses for example during an infection. However, prolonged or excessive elevation of glucocorticoids as occurring during recurrent or chronic stress can negatively impact various aspects of immune cell functions and may therefore contribute to disease development and progression. The precise mechanisms and course of events leading to the suppression of immune functions during chronic stress and how these effects result in certain diseases remains poorly understood.The aim of the present thesis was to further analyze underlying mechanisms of chronic stress-related immunosuppression focusing on T cell-mediated immunity. In order to mimic recurrent stress experiences, a well-established mouse model of chronic social stress termed social disruption stress (SDR) was chosen for the experiments conducted in chapters 2 and 3. Pharmacological intervention (i.e. the blockage of the respective receptors) in these experiments allowed us to differentiate between the impact of glucocorticoids and catecholamines, the main mediators of stress responses during chronic exposure.Chapter 2 focuses on the impact of chronic social stress on the outcome of virus-specific cytotoxic TCD8+ cell (CTL) responses in mice after infection with lymphocytic choriomeningitis virus (LCMV). Taking into account that the duration of stress exposure and also the timing of stress relative to an immune challenge can greatly impact the outcome of immune alterations, we directly compare different stress procedures. We show that social stress impacts the generation of IFN-g-producing, virus-specific TCD8+ splenocytes only when applied prior to virus infection. We further demonstrate that during a prolonged stress exposure glucocorticoid hormones strongly impact the proliferation capacity of TCD8+ cells in the spleen of infected mice. This impairment results most probably from reduced TCD8+ activation as well as an impaired cytokine secretion profile. The reduced expansion of TCD8+ cells appears to be organ specific, as we found no such alterations in the inguinal lymph node or in the blood or peripheral tissues such as the liver and lung. A possible explanation for the organ-specific decline in TCD8+ cell expansion could be an altered migration capacity of splenic TCD8+ cells as demonstrated by adoptive T cell transfer experiments.Chapter 3 describes the impact of chronic social stress on the migratory capability of skin dendritic cells (DCs). Skin DC and in particular Langerhans cells are known as critical inducers of cutaneous immune responses. Glucocorticoid-mediated impairment of DC function has been in the focus of recent investigations. To directly investigate the consequences of chronic stress on skin DC function, we performed contact allergen-induced skin sensitization assays using the fluorescent dye fluorescein isothiocyanate (FITC), which allowed us to trace the migration of skin CD11c+ DCs in vivo. Our data reveal that chronic social stress applied prior to skin sensitization suppresses the migratory capability of epidermal CD11c+ DCs to regional lymph nodes. Using an ex vivo ear skin explant model of skin DC migration we further show that the altered migration is presumably a result of an impaired mobilisation of CD11c+ DCs from the skin.In chapter 4 we characterize phenotypic changes in T lymphocyte subsets in the peripheral blood of severely traumatized human patients. Posttraumatic stress disorder (PTSD) is associated with an enhanced susceptibility to various somatic diseases although the exact mechanisms linking traumatic stress to subsequent physical health problems have remained elusive. Our results demonstrate that PTSD patients exhibit a profoundly altered composition of the peripheral T cell compartment characterized by a reduction in naive T lymphocytes, and increased proportion of central (TCM) and effector memory (TEM) cells. Furthermore, we show that subjects with PTSD display a substantial reduction of peripheral regulatory T cells (Treg). To a smaller extent, these findings are also observed in trauma-exposed non-PTSD individuals, indicating a cumulative effect of traumatic stress on T cell distribution.