Abstract
The precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not always well understood. We hypothesized that highly immunogenic viral vectors with identical cell entry pathways but unique replication mechanisms differentially infect and activate DCs to promote antigen presentation and activation of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (vesicular stomatitis virus; VSV) and an alphavirus-rhabdovirus hybrid vector (virus-like vesicles; VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8+ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication but were independent of interferon receptor signaling. Additionally, the ability of the alphavirus-based vector to generate functional CD8+ T cells in the absence of replication relied on cDC1 cells. These results highlight the differential activation of DCs following infection with unique viral vectors and indicate potentially discrete roles of DC subtypes in activating the immune response following immunization with vectors that have distinct replication mechanisms.
Highlights
Vaccination approaches that aim to activate CD8+ T cells benefit from using virus-based platforms, as live viral vectors mimic infection with a virus and generate strong cellular immune responses
Dendritic cells (DCs) can be subdivided into two subtypes of conventional DCs, plasmacytoid DCs, or monocyte-derived DCs19. cDC1 are associated with strong CD8+ T cell activation and are the most efficient subset for crosspresenting antigens[20], while cDC2 promote the activation of CD4+ T cells as well as memory CD8+ T cells21. pDCs are traditionally known for type I interferon (IFN) production, but these cells have important antigen presentation functions[22]
Flt3L DCs were more susceptible to virus infection than GM-CSF-derived antigen-presenting cells (APCs), which is consistent with previous vesicular stomatitis virus (VSV) studies[52]
Summary
Vaccination approaches that aim to activate CD8+ T cells benefit from using virus-based platforms, as live viral vectors mimic infection with a virus and generate strong cellular immune responses. Despite the extensive evaluation of many viral vectors as preclinical vaccine candidates, it is not always known how these vectors successfully activate a protective immune response. Specific dendritic cell (DC) subtypes play critical roles in priming immune responses and controlling virus infection, but their functions in generating effective immunity following vaccination with viral vectors are not well understood. Viruses may infect different DC subtypes leading to unique immune activation profiles[17]. PDCs are traditionally known for type I interferon (IFN) production, but these cells have important antigen presentation functions[22] DCs can be subdivided into two subtypes of conventional DCs (cDC1, cDC2), plasmacytoid DCs (pDC), or monocyte-derived DCs (moDC)19. cDC1 are associated with strong CD8+ T cell activation and are the most efficient subset for crosspresenting antigens[20], while cDC2 promote the activation of CD4+ T cells as well as memory CD8+ T cells21. pDCs are traditionally known for type I interferon (IFN) production, but these cells have important antigen presentation functions[22]
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