Regulation of guinea-pig immune functions by interleukin 2: critical role of natural killer activity in acute HSV-2 genital infection.

We have previously demonstrated that recombinant interleukin 2 (rIL 2) has a protective effect against acute HSV-2 infection in guinea pigs with a biphasic dose response which peaked between 4 and 20 X 10(4) U/kg, whereas 8 X 10(5) U/kg showed no effect on disease. Animals that escaped infection appeared lack immunologic memory to HSV-2, suggesting a nonspecific immune mechanism. In this study we have found that NK activity of fresh splenocytes measured against HSV-2 infected human foreskin fibroblast (HFF) is stimulated in vitro and in vivo by rIL 2 in a biphasic dose range similar to that determined for protection against disease. In contrast, lymphokine-activated killer (LAK)-mediated lysis of P815 showed a linear response to increasing concentrations of rIL 2 both in vitro and in vivo. Transfer of LAK cells did not alter the rate of infection after HSV-2 challenge. Anti-asialo GM-1 eliminated rIL 2 protection against HSV-2 infection. It also blocked HSV-2/HFF lysis and partially decreased P815 lysis in vitro; however, in vivo it inhibited both natural killer (NK) activity and LAK generation, failing to distinguish which of the lytic cells was responsible for the effect against infection. Early IgG production (7 days post-infection) was enhanced by rIL 2 administration before viral inoculation, but it did not influence the rate of infection as compared with controls. Polyclonal IgM secretion was not found to play a role in acute protection. Circulating serum interferon levels were enhanced with increasing concentrations of rIL 2 but did not correlate with the biphasic dose curve for protection. Therefore of these mechanisms the one that is most closely related to the protective effect of rIL 2 against primary HSV-2 infection appears to be NK-mediated lysis, although the other mechanisms may add to this effect.