Dendritic Cell Maturation, but Not CD8+ T Cell Induction, Is Dependent on Type I IFN Signaling during Vaccination with Adenovirus Vectors

Abstract

To understand how vaccines initiate adaptive immune responses, it is necessary to study how they interact with APCs such as dendritic cells (DCs). In this study, we analyzed interactions between recombinant adenovirus (Ad) vectors and mouse DCs. Mouse bone marrow-derived DCs transduced with Ad vectors produced type I IFN, which promoted the maturation of both transduced and bystander DCs. DCs transduced with a vector derived from a chimpanzee Ad serotype (AdC68) produced more type I IFN and matured more efficiently compared with DCs transduced with a vector derived from a human Ad serotype (AdHu5). Both vectors stimulated type I IFN production independently of viral transcription, replication, and TLR signaling. However, each vector induced type I IFN through distinct pathways; whereas AdHu5 vectors required phosphoinositide-3-OH kinase for type I IFN induction, AdC68 vectors did not. Both vectors induced strong transgene product-specific CD8+ T cell responses in wild-type mice. DCs isolated from mice that have a defect in type I IFN signaling failed to undergo full maturation after Ad vaccination, but surprisingly, these mice mounted strong transgene product-specific CD8+ T cell responses. In these mice, we were able to detect a small number of transduced DCs that expressed high levels of costimulatory molecules, and these DCs were able to stimulate transgene product-specific CD8+ T cells. Thus, type I IFN signaling is an important component of Ad-mediated DC maturation but is dispensable during the generation of transgene product-specific CD8+ T cell responses.

Type I IFN Signaling on Both B and CD4 T Cells Is Required for Protective Antibody Response to Adenovirus

“…1B) increased over time and peaked at 12 h after infection. Consistent with the previous observations (19,20), these results indicate that type I IFNs can be induced rapidly upon adenoviral infection in vivo.…”

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

“…38 For example, chimpanzee-derived Ads have been shown to induce greater levels of type I IFNs than do HAd5 vectors both in vitro and in vivo. 72,73 This may partially explain the increased immune response to SAd23 observed in this study. Importantly both HAd3 and SAd23 specifically activated the alternative complement pathway in human serum, and the induction of IL-1a, MCP-1 and MIP-1b, and IL-10 were in part complement dependent in our mouse model.…”

Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

“…Another possible mechanism which could result in an abrogation of the proinflammatory cytokine response to FPV was a defect in the maturation in IFNAR Ϫ/Ϫ DCs. Previous studies with viruses including human adenovirus (AdV) have shown that DCs from IFNAR Ϫ/Ϫ mice are incapable of undergoing full maturation in response to viral infection (22,47) although other studies indicate little or no defect in DC maturation (33). The results of our experiments showed no obvious defect in the maturation of DCs from IFNAR Ϫ/Ϫ mice in response to FPV as upregulation of CD40, CD80, and CD86 was similar to that observed in the control groups, and the profiles were also broadly the same as those seen following stimulation with the synthetic TLR9 agonist, CpG.…”