Coronavirus-induced acute hepatitis is a complex event and the role of different components of the immune system with regard to defined viral proteins and the course of the infection is not yet clear. We have analysed the cytotoxic T-lymphocyte (CTL) response in mouse hepatitis virus (MHV-A59) infection. Surprisingly, we detected only a very clear virus-specific major histocompatibility complex (MHC) class II-restricted cytotoxicity in mice infected with MHV-A59. We found no evidence of activation of the classical CD8+ MHC class I-restricted CTL. The virus-specific CD4+ CTL derived from two different mouse strains having different MHC haplotypes recognized the same immunodominant epitope. This epitope, comprising the amino acid residues 329-343 of the viral S-glycoprotein, was recognized both at the polyclonal level and by virus-specific CTL clones. Transfer studies using a MHV-A59-specific CD4+ CTL clone showed significant protection against a lethal challenge with MHV-A59, implicating that these CD4+ CTL play a pivotal role in the protection against MHV-A59 infections.