The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration

•CpG dinucleotides in the AAV vector genome negatively impacts gene transfer and expression.•With an antibody-encoding transgene, this effect is observed at 24 h after AAV administration.•Plasmacytoid DC-like myeloid cells expressing Fc receptor are activated after AAV administration. AAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2–3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population.