AUTHOR=Ulrich-Lewis Justin Theophilus , Draves Kevin E. , Roe Kelsey , O’Connor Megan A. , Clark Edward A. , Fuller Deborah Heydenburg 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.861710

DOI=10.3389/fimmu.2022.861710

ISSN=1664-3224

ABSTRACT=<p>DNA vaccines elicit antibody, T helper cell responses and CD8<sup>+</sup> T cell responses. Currently, little is known about the mechanism that DNA vaccines employ to induce adaptive immune responses. Prior studies have demonstrated that <italic>stimulator of interferon genes</italic> (<italic>STING</italic>) and conventional dendritic cells (cDCs) play critical roles in DNA vaccine induced antibody and T cell responses. <italic>STING</italic> activation by double stranded (dsDNA) sensing proteins initiate the production of type I interferon (IFN),but the DC-intrinsic effect of <italic>STING</italic> signaling is still unclear. Here, we investigated the role of <italic>STING</italic> within cDCs on DNA vaccine induction of antibody and T cell responses. <italic>STING</italic> knockout (<italic>STING<sup>-/-</sup></italic>) and conditional knockout mice that lack <italic>STING</italic> in cDCs (<italic>cDC STING cKO</italic>), were immunized intramuscularly with a DNA vaccine that expressed influenza A nucleoprotein (pNP). Both <italic>STING<sup>-/-</sup></italic> and <italic>cDC STING cKO</italic> mice had significantly lower type I T helper (Th1) type antibody (anti-NP IgG<sub>2C</sub>) responses and lower frequencies of Th1 associated T cells (NP-specific IFN-γ<sup>+</sup>CD4<sup>+</sup> T cells) post-immunization than wild type (WT) and <italic>cDC STING littermate control</italic> mice. In contrast, all mice had similar Th2-type NP-specific (IgG<sub>1</sub>) antibody titers. <italic>STING<sup>-/-</sup></italic> mice developed significantly lower polyfunctional CD8<sup>+</sup> T cells than WT, <italic>cDC STING cKO</italic> and <italic>cDC STING littermate control</italic> mice. These findings suggest that <italic>STING</italic> within cDCs mediates DNA vaccine induction of type I T helper responses including IFN-γ<sup>+</sup>CD4<sup>+</sup> T cells, and Th1-type IgG<sub>2C</sub> antibody responses. The induction of CD8<sup>+</sup> effector cell responses also require <italic>STING</italic>, but not within cDCs. These findings are the first to show that <italic>STING</italic> 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.</p>