Analysis of MHC Class I Processing Pathways That Generate a Response to Vaccinia Virus Late Proteins

Use of recombinant viral vectors encoding nonnative Ags is an attractive mechanism for the generation of protective Ab, CD4⁺ T cell (T_CD4+), and CD8⁺ T cell (T_CD8+) responses in vivo following immunization. However, the life cycle and tropism of the viral vector, and its interactions with various components of the immune system, must be fully understood to maximize the efficacy of any vaccination strategies. Ab and T_CD4+ responses typically target native Ags driven by late promoters in vaccinia virus (VACV)–based vectors. However, it has been demonstrated that model Ags driven by late promoters in recombinant VACV vectors do not stimulate T_CD8+ responses, whereas identical Ags driven by early promoters stimulate strong responses. Conversely, T_CD8+ can be generated against some natural late VACV Ags. We explored this dichotomy by investigating the Ag presentation pathways responsible for presentation of natural late VACV Ags in mice. We found that all of the late VACV Ags we examined could be cross-primed (i.e., presented by uninfected professional APC), as well as directly presented by infected dendritic cell populations. However, one Ag was only presented by professional APC populations and was not the target of a protective T_CD8+ response. Therefore, there is no generalized blockade in Ag presentation of late VACV Ags, and expression of nonnative Ags driven by a late promoter allows production of large quantities of Ag that may allow simultaneous targeting of both T_CD4+ and Ab responses, as well as T_CD8+ responses, in the future.