Male BALB/c mice inoculated with 6 X 10(4) plaque-forming units (pfu) coxsackievirus, group B, type 3 (CVB3), develop myocarditis within 7 days. Two cytolytic T lymphocyte (CTL) populations arise in infected animals. One population belongs to the Lyt 2+ T (cytolytic/suppressor) lymphocyte subset and reacts specifically with uninfected heart cells (autoreactive CTLs, ACTLs), whereas the other belongs to the L3T4+ T (helper) lymphocyte subset and reacts with infected targets (virus-specific CTLs, VSCTLs). Although both immune T lymphocyte populations can induce cardiac inflammation in vivo, ACTLs predominantly cause tissue injury. VSCTL generation can be inhibited by either anti-Tac (antibody to the interleukin 2 [IL-2] receptor) or anti-Iad but not by anti-IAk, indicating that this response is probably both IL-2-dependent and Class II (major histocompatibility complex [MHC] antigen restricted. ACTL generation is independent of IL-2, because neither anti-Tac or cyclosporin A inhibit this response.