Mature T helper cell subsets have been divided into the TH1 and TH2 subsets. TH1 cells produce interleukin (IL)-2 and interferon (IFN)-gamma, and are critical for development of cell-mediated immune responses. TH2 cells produce IL-4, IL-5, IL-6, and IL-10, cytokines that drive humoral immune responses. The two subsets are controlled by a number of factors, including other cytokines produced by macrophage/monocytes (IL-12), in addition to TH1 and TH2 cells exerting negative feedback on each other. It has been postulated that a balance between TH1 and TH2 cell function is critical for immune responses to pathogens. Recently, it has been strongly suggested that poor prognosis in HIV-infected individuals correlates with a loss of dominant TH1 cell-mediated immune responses, increased production of TH2 cytokines and increased antibody titers to HIV. Unknown factors are hypothesized to affect the shift in TH1-TH2 cell balance. We have determined that pheromones emitted by stressed mice can affect immune responses in BALB/c mice. Cell-mediated immune responses are suppressed in stress odor-exposed mice, whereas humoral immune responses are enhanced. Additionally, preliminary data indicate that IL-2 production is decreased, and IL-4 production enhanced in stress odor- exposed animals. Thus, it appears that psychosocial factors can affect the balance of TH1 and TH2 cells. We have noted that this does not occur in all strains of mice; this may reflect a degree of heterogeneity that also exists in humans (who do not all respond to HIV infection with similar kinetics). The proposed research is aimed at further understanding the apparent shift in T helper cell subsets in BALB/c mice. We propose to examine immune responses to a soluble protein antigen, as well as to herpes simplex virus (HSV)-type 1, a serious human pathogen, particularly in immunocompromised individuals. We further propose that the effects of stress odor-exposure may involve glucocorticoids, and provide evidence that the glucocorticoid antagonist RU486 may abrogate the effects of stress odor-exposure on the alteration in TH2 cytokines. The study of stress-induced changes in TH1 and TH2 cells and immunological effector mechanisms is important because it may provide a basis for explaining the reports that AIDS patients who are stressed or experiencing psychological discomfort may have poorer prognoses. Further, the experiments will provide new information regarding mechanisms of neural- immune interactions.