We have investigated the induction and role of natural killer (NK) activity in lymphocytic choriomeningitis virus (LCMV)-infected beta(2)-microgrobulin-deficient (beta(2)m(-)) mice. We demonstrate that LCMV infection is more effective than polyinosinic:polycytidylic acid (poly I:C) at stimulating NK activity in beta(2)m(-) mice. In addition, beta(2)m(-) NK cells respond poorly to in vitro treatment with IL-12. The target specificity of the virally induced NK cells is similar to that previously reported for chemically induced beta(2)m(-) NK cells. In both cases they can lyse YAC-1 tumor cells but are unable to kill beta(2)m(-) or beta(2)m(+) T cell blasts. We have also found that the time course of induction of MK and cytotoxic T lymphocyte (CTL) activity by LCMV in beta(2)m(-) mice is delayed compared with normal mice. Maximal NK and CTL activity is attained at day 8 and 10 post-infection respectively in beta(2)m(-) mice compared with day 4 and 6-8 in B6 mice. Whereas normal mice die similar to 7 days following intracranial infection with LCMV, the course of disease in beta(2)m(-) mice is protracted and characterized by a marked loss of body weight. We show that although the CD4(+) CTL response in these mice is intimately involved in mediating weight loss, the virus-induced NK cells do not appear to play a role in the disease.