Neuroendocrine-derived peptides and hormones have long been recognized as immune modulators. More specifically, glucocorticoids, such as cortisol in humans and corticosterone in rodents, which are elevated during conditions of psychological stress, are generally immunosuppressive. At the cellular level, glucocorticoids impair cytokine production, NK cell cytotoxicity, microglial expression of MHC Class I, and CD8+ T cell proliferation and migration to the site of infection. These findings have dramatic effects at the organismal level. For example, glucocorticoids have previously been implicated in reduced vaccine-elicited immune responses, delayed wound healing, and increased pathology/mortality during herpes simplex virus (HSV) infection. Earlier work has investigated the effects of stress on the immune response to HSV following infection via the footpad, ocular and intranasal routes.;Although the aforementioned studies provided valuable insight into the mechanisms by which glucocorticoids modulate cell-mediated immune responses, they neglected to examine the immune response at the site of initial infection, focusing instead on the virus' progression to the nervous tissue. Additionally, there have yet to be any published studies examining the effects of psychological stress on the immune response at mucosal sites. In the studies described herein, we used a well-defined murine model of restraint stress to define the effects of stress during primary HSV-1 infection within nasopharyngeal-associated lymphoid tissue and vaginal mucosa. These studies revealed that corticosterone exerted a two-pronged attack on the initial mucosal immune response via a glucocorticoid-receptor mediated mechanism. First, restraint stress-induced increases in serum corticosterone decreased the number of immune cells at the site of infection, thereby impairing clearance of the infection and allowing for increased titers of HSV. These results could be mimicked with either the provision of exogenous corticosterone via the drinking water, or by surgically reducing the number of cells within the mucosa prior to infection. In addition, the decrease in cellularity was partially prevented following pharmacological blockade of the type II glucocorticoid receptor. Second, glucocorticoids reduced the number of CD8+ T cells which undergo degranulation, or produce interferon-gamma within the draining lymph nodes. These findings have serious clinical implications, in that increased viral titers and associated pathophysiology increase the length of infection, thereby augmenting the risk of transmission to non-infected individuals. Additionally, an impaired immune response to intranasally-acquired antigens may compromise the efficacy of aerosolized vaccines.;Having characterized the effects of stress at the organismal level, we next turned our attention to the effects of ex vivo corticosterone exposure on CD8+ T cells. Although there are numerous reports of glucocorticoids impairing CD8+ T cell activity (including proliferation, cytokine production and the ability to lyse target cells), there are no studies focusing on specific mechanisms by which granule-mediated cytotoxicity is impaired. Using antigen-specific CD8+ T cells, of either a naive and memory phenotype, we assessed the ability of cells to respond to antigen in the presence of physiologically-relevant levels of corticosterone. Naive CD8+ T cells that had been exposed to corticosterone failed to acquire an activated phenotype (CD25+, CD69 +) following stimulation with immobilized anti-CD3/anti-CD28, and were subsequently unable to degranulate and lyse peptide-pulsed target cells. Further examination of these cells revealed that their function was inhibited by increased expression of the inhibitory co-stimulatory molecule, CTLA-4. Surprisingly, CD8+ T cells with a memory phenotype (CD62L lo, CD44hi) were still able to degranulate in the presence of corticosterone, and were not susceptible to increased CTLA-4 expression. These findings are the first to suggest that cells with a memory phenotype are more resilient to the effects of glucocorticoids.;Taken together, the studies described in this thesis demonstrate that stress-induced immunosuppression during mucosal HSV-1 infection begins with a failure to efficiently clear virus at the initial site of infection through both direct and indirect effects of glucocorticoids. Additionally, we report a CD8+ T cell-specific mechanism by which glucocorticoids inhibit the immune response. These findings help explain the increase in HSV incidence and pathology in individuals experiencing psychological stress.