Experimental preemptive immunotherapy of murine cytomegalovirus disease with CD8 T-cell lines specific for ppM83 and pM84, the two homologs of human cytomegalovirus tegument protein ppUL83 (pp65)

CD8 T cells are the principal antiviral effecters controlling cytomegalovir us (CMV) infection. For human CMV, the virion tegument protein ppUL83 (pp65 ) has been identified as a source of immunodominant peptides and is regarde d as a candidate for cytoimmunotherapy and vaccination. Two sequence homolo gs of ppUL83 are known for murine CMV, namely the virion protein ppM83 (pp1 05) expressed late in the viral replication cycle and the nonstructural pro tein pM84 (p65) expressed in the early phase. Here we show that ppM83, unli ke ppUL83, is not delivered into the antigen presentation pathway after vir us penetration before or in absence of viral gene expression, while other v irion proteins of murine CMV are processed along this route. In cytokine se cretion-based assays, ppM83 and pM84 appeared to barely contribute to the a cute immune response and to immunological memory. Specifically, the frequen cies of M83 and M84 peptide-specific CD8 T cells were low and undetectable, respectively. Nonetheless, in a murine model of cytoimmunotherapy of letha l CMV disease, M83 and M84 peptide-specific cytolytic T-cell lines proved t o be highly efficient in resolving productive infection in multiple organs of cell transfer recipients. These findings demonstrate that proteins which fail to prime a quantitatively dominant immune response can nevertheless r epresent relevant antigens in the effector phase. We conclude that quantita tive and qualitative immunodominance are not necessarily correlated. As a c onsequence of these findings, there is no longer a rationale for considerin g T-cell abundance as the key criterion for choosing specificities to be in cluded in immunotherapy and immunoprophylaxis of CMV disease and of viral i nfections in general.