Interferon-Independent Activities of Mammalian STING Mediate Antiviral Response and Tumor Immune Evasion

Immunity. 2020 Jul 14;53(1):115-126.e5. doi: 10.1016/j.immuni.2020.06.009. Epub 2020 Jul 7.

Abstract

Type I interferon (IFN) response is commonly recognized as the main signaling activity of STING. Here, we generate the Sting1S365A/S365A mutant mouse that precisely ablates IFN-dependent activities while preserving IFN-independent activities of STING. StingS365A/S365A mice protect against HSV-1 infection, despite lacking the STING-mediated IFN response. This challenges the prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis reveals widespread IFN-independent activities of STING in macrophages and T cells, and STING activities in T cells are predominantly IFN independent. In mouse tumor models, T cells in the tumor experience substantial cell death that is in part mediated by IFN-independent activities of STING. We found that the tumor induces STING-mediated cell death in T cells to evade immune control. Our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive immunity.

Keywords: HSV-1; IFN; STING; T cells; antiviral response; cancer immunology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Cell Line
  • Female
  • HEK293 Cells
  • Herpes Simplex / immunology
  • Herpes Simplex / prevention & control
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Immunity, Innate / immunology
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology*
  • Macrophages / immunology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • Tumor Escape / immunology*

Substances

  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse