Stress-induced effects on integral immune components involved in herpes simplex virus (HSV)-specific memory cytotoxic...

We have previously shown that restraint stress suppresses the activation of a polyclonal population of herpes simplex virus (HSV)-specific memory cytotoxic T lymphocytes (CTLm) to the lytic phenotype. We have extended these findings by demonstrating that this suppression occurs in two distinct HSV-specific CTLm populations that are generated in C57BL/6 mice in response to HSV infection and that recognize distinct epitopes expressed early in the HSV infection cycle. Moreover, these CTLm exhibited different levels of susceptibility to stress-induced suppression of activation. To elucidate the mechanisms responsible for this suppression, we have examined the effect of restraint on immunological components that are necessary for CTLm activation. We demonstrated that the expression of the T cell receptor (TCR), IL-2 receptor (IL-2R), and other accessory molecules involved in T cell activation were similar on CD8(+) T cell populations from both control and restrained groups of mice. However, splenic lymphoid cells from restrained mice generated significantly lower levels of IL-2, IL-4, IL-6, and gamma interferon (IFN-gamma) than did those cells from control, nonrestrained mice. The reduced ability to activate HSV-specific CTLm from mice subjected to restraint could be overcome by increasing the cell density and, thus, the lymphokine concentrations in these cultures. Overall, these findings suggest that restraint stress does not affect the inherent ability of an HSV-specific CTLm to be activated to the lytic phenotype; rather, the availability of lymphokines necessary to drive the activation process may be the limiting factor as to whether or not CTLm activation occurs. This stress-induced suppression of lymphokine production may not only play a role in inhibiting HSV-specific CTL activation but may also contribute to a diminution in the responsiveness and function of other components of immunological memory that are dependent on the presence of lymphokines.