Direct Antigen Presentation is the Canonical Pathway of Cytomegalovirus CD8 T-cell Priming Regulated by Balanced Immune Evasion Mounting a Strong Antiviral Response

CD8 T cells are the main antiviral effectors of the adaptive immune response to cytomegaloviruses (CMVs) in confining acute infection and in long-term surveillance of latent infection. An unresolved issue of debate, with diametrically opposite conclusions, is the mechanism by which CMV-specific naive CD8 T cells are primed. The idea of priming by antigen cross-presentation through uninfected professional antigen presenting cells taking up viral proteins derived from infected cells was based on the observation that the net response is not improved when direct presentation is enhanced by deletion of viral immune evasion genes affecting the classical MHC class-I pathway of antigen presentation. Redundance of priming mechanisms has been demonstrated by experimental models in which either pathway has been rendered inaccessible, so that both pathways are, in principle, capable of priming CD8 T cells. For studying CMV-specific priming in the normal host competent in both antigen presentation pathways, we took the novel approach to enhance instead of delete immune evasion protein expression. Surprisingly, the net magnitude of the CD8 T-cell response in the regional lymph node draining a local site of infection was identical for the contrasts of reduced or enhanced direct antigen presentation. At first glance, this may lead one to conclude that direct presentation plays no role in priming. This interpretation, however, is incompatible with the finding that an intermediate extent of direct antigen presentation, as it exists for wild-type virus, resulted in the best CD8 T-cell response. Our findings thus revealed an essential positive role of a balanced viral immune evasion in mounting a strong antiviral immune response. This novel insight sheds a completely new light on the acquisition of viral immune evasion genes during virus-host co-evolution.