Oligopeptides of the highly conserved herpes virus glycoprotein B (gB) were expressed from DNA fragments of the EBV gB (BALF4) and HSV-2 gB open reading frames as fusion proteins with the lambda CII protein and beta-galactosidase (GZ), respectively, in Escherichia coli. After immunopurification using anti-gB or anti-GZ affinity columns, the fusion proteins were used in vitro to stimulate human peripheral blood lymphocytes (PBL) or murine lymph node cells that have been primed with EBV, HSV-1, HSV-2, VZV or HCMV (all human herpes viruses) to proliferate. Results obtained in BALB/c mice indicate that different herpes viruses induce different levels of T-cell response to each other and to gB, over a range of type-specific and cross-reactive T-cell epitopes. There is a lack of correlation of immunogenicity and antigenicity in the generation of T-cell responses between some of the viruses. Major T-cell epitopes are located at the C terminal half of the gB molecule. The T-cell response to gB in healthy individuals seropositive for various combinations of the five herpes viruses differed markedly from individual to individual, even when they are seropositive to the same set of herpes viruses. However, two individuals with high proliferative T-cell response to VZV and sharing HLA A2, B7, DR2 and DQw1 are also good responders for cross-reactive gB/fragments and for virus antigen of all the five herpes viruses. Therefore the data obtained demonstrated that the MHC and the immune interaction arising from cross-reactive T-cell response evoked by other herpes viruses may determine the pathogenesis of a herpes virus infection.