MyD88/CD40 Genetic Adjuvant Function in Cutaneous Atypical Antigen-Presenting Cells Contributes to DNA Vaccine Immunogenicity
Authors
Matthew R. Collinson-Pautz, Kevin M. Slawin, Jonathan M. Levitt, David M. Spencer
Institution
Baylor College of Medicine, Houston, TX
Country
United States
Year
2016
Journal
PLOS One
Abstract
Therapeutic DNA-based vaccines aim to prime an adaptive host immune response against
tumor-associated antigens, eliminating cancer cells primarily through CD8+ cytotoxic T cellmediated
destruction. To be optimally effective, immunological adjuvants are required for
the activation of tumor-specific CD8+ T cells responses by DNA vaccination. Here, we
describe enhanced anti-tumor efficacy of an in vivo electroporation-delivered DNA vaccine
by inclusion of a genetically encoded chimeric MyD88/CD40 (MC) adjuvant, which integrates
both innate and adaptive immune signaling pathways. When incorporated into a
DNA vaccine, signaling by the MC adjuvant increased antigen-specific CD8+ T cells and
promoted elimination of pre-established tumors. Interestingly, MC-enhanced vaccine efficacy
did not require direct-expression of either antigen or adjuvant by local antigen-presenting
cells, but rather our data supports a key role for MC function in ªatypicalº antigenpresenting
cells of skin. In particular, MC adjuvant-modified keratinocytes increased inflammatory
cytokine secretion, upregulated surface MHC class I, and were able to increase in
vitro and in vivo priming of antigen-specific CD8+ T cells. Furthermore, in the absence of
critical CD8α+/CD103+ cross-priming dendritic cells, MC was still able to promote immune
priming in vivo, albeit at a reduced level. Altogether, our data support a mechanism by
which MC signaling activates an inflammatory phenotype in atypical antigen-presenting
cells within the cutaneous vaccination site, leading to an enhanced CD8+ T cell response
against DNA vaccine-encoded antigens, through both CD8α+/CD103+ dendritic cell-dependent
and independent pathways.