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 that <i>stimulator of interferon genes</i> (<i>STING</i>) and conventional dendritic cells (cDCs) play critical roles in DNA vaccine induced antibody and T cell responses. <i>STING</i> activation by double stranded (dsDNA) sensing proteins initiate the production of type I interferon (IFN),but the DC-intrinsic effect of <i>STING</i> signaling is still unclear. Here, we investigated the role of <i>STING</i> within cDCs on DNA vaccine induction of antibody and T cell responses. <i>STING</i> knockout (<i>STING^-/-</i> ) and conditional knockout mice that lack <i>STING</i> in cDCs (<i>cDC STING cKO</i>), were immunized intramuscularly with a DNA vaccine that expressed influenza A nucleoprotein (pNP). Both <i>STING^-/-</i> and <i>cDC STING cKO</i> mice had significantly lower type I T helper (Th1) type antibody (anti-NP IgG_2C) responses and lower frequencies of Th1 associated T cells (NP-specific IFN-γ⁺CD4⁺ T cells) post-immunization than wild type (WT) and <i>cDC STING littermate control</i> mice. In contrast, all mice had similar Th2-type NP-specific (IgG₁) antibody titers. <i>STING^-/-</i> mice developed significantly lower polyfunctional CD8⁺ T cells than WT, <i>cDC STING cKO</i> and <i>cDC STING littermate control</i> mice. These findings suggest that <i>STING</i> within cDCs mediates DNA vaccine induction of type I T helper responses including IFN-γ⁺CD4⁺ T cells, and Th1-type IgG_2C antibody responses. The induction of CD8⁺ effector cell responses also require <i>STING</i>, but not within cDCs. These findings are the first to show that <i>STING</i> is required within cDCs to mediate DNA vaccine induced Th1 immune responses and provide new insight into the mechanism whereby DNA vaccines induce Th1 responses.