STING Is Required in Conventional Dendritic Cells for DNA Vaccine Induction of Type I T Helper Cell- Dependent Antibody Responses

Abstract

DNA vaccines elicit antibody, T helper cell responses and CD8+T cell responses. Currently, little is known about the mechanism that DNA vaccines employ to induce adaptive immune responses. Prior studies have demonstrated thatstimulator of interferon genes(STING) and conventional dendritic cells (cDCs) play critical roles in DNA vaccine induced antibody and T cell responses.STINGactivation by double stranded (dsDNA) sensing proteins initiate the production of type I interferon (IFN),but the DC-intrinsic effect ofSTINGsignaling is still unclear. Here, we investigated the role ofSTINGwithin cDCs on DNA vaccine induction of antibody and T cell responses.STINGknockout (STING-/-) and conditional knockout mice that lackSTINGin cDCs (cDC STING cKO), were immunized intramuscularly with a DNA vaccine that expressed influenza A nucleoprotein (pNP). BothSTING-/-andcDC STING cKOmice had significantly lower type I T helper (Th1) type antibody (anti-NP IgG2C) responses and lower frequencies of Th1 associated T cells (NP-specific IFN-γ+CD4+T cells) post-immunization than wild type (WT) andcDC STING littermate controlmice. In contrast, all mice had similar Th2-type NP-specific (IgG1) antibody titers.STING-/-mice developed significantly lower polyfunctional CD8+T cells than WT,cDC STING cKOandcDC STING littermate controlmice. These findings suggest thatSTINGwithin cDCs mediates DNA vaccine induction of type I T helper responses including IFN-γ+CD4+T cells, and Th1-type IgG2Cantibody responses. The induction of CD8+effector cell responses also requireSTING, but not within cDCs. These findings are the first to show thatSTINGis required within cDCs to mediate DNA vaccine induced Th1 immune responses and provide new insight into the mechanism whereby DNA vaccines induce Th1 responses.