Stress-induced glucocorticoids impair dendritic cell function, compromising CD8+ T cell responses to herpes simplex virus

Chronic psychological stress has long been known to be potently immunosuppressive. Although several studies have found that stress suppresses CD8+ T cell-mediated immunity to herpes simplex virus (HSV), the underlying mechanisms of this suppression and the specific cellular targets of neuroendocrine hormones are unknown.;In order to generate an antigen-specific CD8+ T cell response, a protein must be processed into an 8-10 amino acid long antigenic peptide. These peptides are presented to antigen-specific CD8+ T cells on the appropriate MHC class I molecule by antigen-presenting cells (APC) that express the necessary costimulatory molecules. Interfering with any of these steps can result in weaker or slower CD8+ T cell responses, thus impairing the ability of the host to control the growth and spread of a pathogen.;Dendritic cells (DC) are the most potent APC and are critical in the initiation of CD8+ T cell responses. While neuroendocrine hormones, including stress-induced glucocorticoids (GC), have strong suppressive effects on T cell responses, it is not known whether these effects are mediated by direct effects on T cells themselves or occur indirectly via effects on the DC that are necessary for T cell activation.;The effects of stress-induced GC on DC function were investigated by treating murine DC with the rodent GC corticosterone (CORT) and determining the effects of CORT on the responses of DC to lipopolysaccharide (LPS). These studies found that CORT suppresses several components of the DC response to LPS, with effects on DC maturation, endocytosis, and cytokine production. The net result of the effects of CORT on DC is that DC are rendered less efficient for T cell priming.;These studies were extended in vivo to determine the effects of stress on DC function during an HSV infection. By using a model of restraint stress in which mice were subjected to stress during the earliest part of infection, we were able to determine the effects of stress on the first stages of the immune response and the consequences of these effects on the subsequent course of infection. In these studies, we found that DC from infected mice were impaired in their ability to stimulate CD8 + T cells ex vivo, while the CD8+ T cell response was impaired in vivo. These impairments were associated with increased viral loads, delayed viral clearance, and delayed resolution of viral lesions. The effects of stress on the CD8+ T cell response are mediated by CORT because they can be blocked using a GC receptor (GR) antagonist. Using a line of mice whose T cells do not express GR (GR-TKO), we were able to determine that CD8+ T cell responses are suppressed by the effects of stress-induced CORT on non-T cells. The identity of these "non-T cells" is likely to be DC, as they are impaired in stressed mice, critical for efficient T cell function, and susceptible to functional impairment by CORT.;The findings presented in this dissertation underscore the central role that DC have in the generation of T cell responses and highlight the importance of DC as a target of neuroendocrine hormones during stress-induced immunosuppression. Therapeutic strategies aimed at modulating T cell responses in stressed individuals must take into account the effects of neuroendocrine hormones on DC function to successfully overcome stress-induced immunosuppression.