Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice: natural killer cell activity in cultured spleen leukocytes concomitant with T-cell-dependent immune interferon production

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Abstract
The characteristics and specificities of spleen and peritoneal cytotoxic cells generated during lymphocytic choriomeningitis virus (LCMV) infection of C3H/St mice were examined. Activated natural killer (NK) cell activity was identified in fresh leukocyte populations from the 2nd-8th days postinfection; virus-specific cytotoxic T cell activity was detected from the 6th-14th days. When leukocytes were cultured overnight at 37.degree. C before assay, T-cell activity was still observed but nonspecific activated NK cell-like cytotoxicity was only detected on the 6th and, to a lesser degree, the 8th day postinfection. Overnight culture of leukocytes taken earlier in the infection eliminated their NK cell activity. Similar activities were seen with spleen cell, plastic-adherent peritoneal cell and nonadherent peritoneal cell populations. The virus-specific cytotoxicity observed with adherent peritoneal cells was due to contamination with cytotoxic T cells, as shown by H-2-restricted cytotoxicity and sensitivity to anti-.theta. antibody and complement. The nonspecific cultured day 6 effector cell from the spleen or peritoneum displayed killing specificities and other physical properties identical to those of activated NK cells but had sensitivities to anti-.theta. antibody and complement intermediate between activated day 3 NK cells and cytotoxic T cells. Culture stable NK-like cells were not found in athymic nude mice, suggesting a T cell-dependent mechanism. Whereas LCMV spleen homogenates contained 10-fold higher levels of interferon at day 2 than at day 6 postinfection, substantially more (nearly 20-fold) interferon was made in cultures of day 6 cells than day 2 cells. Spleen interferon was predominantly type I; the culture interferon was predominantly type II, as shown by acid lability studies. Significant levels of interferon were produced by nylon-wool-passed day 6 spleen cells and virtually all interferon production was eliminated by treatment of day 2 or day 6 cells with antibody to .THETA. antigen and complement, suggesting that T cells produced the interferon in vitro. Athymic nude mice had no culture-stable NK cells 6 days postinfection and spleen cells from them failed to produce significant levels of interferon in vitro. Addition of interferon (type I, fibroblast) to cultured C3H spleen cells reactivated the NK cells in control and D2 spleen cell preparations but did not affect the already elevated levels of cytotoxicity in day 6 cultures, suggesting that the NK cells in the day 6 culture were already activated. T cells responding to LCMV infection secrete interferon type II which causes the continued activation of NK cells in culture. The resulting population of activated NK cells therefore appears to be relatively stable in culture and to express more .THETA. antigen because of this T cell dependence. Although one could mistakenly attribute the nonspecific cytotoxicity observed in these studies to be nonspecific or allospecific cytotoxic T cells or cytotoxic macrophages, more careful examination shows that they are most likely activated NK cells. T cells locally responding to viral antigens in vivo may secrete interferon and locally activate NK cells, which may in turn be responsible for some of the T cell-dependent pathology in LCMV infection.

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