Intracranial infection of normal mice with lymphocytic choriomeningitis virus (LCMV) causes meningitis and death mediated by CD8⁺ major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs). β₂-Microglobulin-deficient mice (β₂M^-/-) do not express functional MHC class I proteins and do not produce significant numbers of CD8⁺ T cells. When β₂M^-/- mice were infected with LCMV, many died from LCMV disease and produced a specific response to LCMV mediated by CD4⁺ CTLs that were class II-restricted. In these mice, CD4⁺ CTLs may compensate for the lack of CD8⁺ CTLs.