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

Abstract

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. ImmunoHorizons, 2019, 3: 559-572.

Direct Priming of CD8+T Cells Persists in the Face of Cowpox Virus Inhibitors of Antigen Presentation

“…Together, these findings suggest that L2 53 elicits CD8 + T cells by cross priming, and this is why the CPXV inhibitors fail to reduce L2 53 -specific responses. These two examples support the evidence from others that priming pathway can differ among antigens, epitopes, and constructs for orthopoxviruses, even if direct priming is most consistently observed ( 8 , 13 , 47 – 50 ). Further, some studies suggest that direct and cross presentation pathways can be utilized sequentially in the priming of epitopes ( 48 , 51 ).…”

Efficient Induction of Cytotoxic T Cells by Viral Vector Vaccination Requires STING-Dependent DC Functions

“…As a consequence late viral antigens such as A19 or D13 induce low CD8 + T cell responses, not only because of a delayed expression kinetic in infected cells, but also due to the detention of late antigens in viral factories ( Figure 4A) (50). Likewise, late antigens showed a reduced availability for cross-presentation by antigen presenting cells during infection ( Figures 4B,C) (50,60,61). On the other hand, our in vivo data correlate with the results obtained from the phenotypical analysis of BMDC maturation (Figure 7).…”

T Cell Surveillance during Cutaneous Viral Infections

“…In addition to CD8 + T cells, CD4 + T cells are also important for controlling VACV infection; however, results differ based on the route of viral inoculation. Moutaftsi et al demonstrated that VACV-specific CD4 + T cells recognize determinants from different viral proteins compared to CD8 + T cells, including viral structural and regulatory proteins expressed at later stages of VACV infection [47,48]. These findings are consistent with a role for cross-presentation during CD4 + T cell activation after the transfer of late VACV proteins to APCs [49].…”