Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality

Immunity. 2016 Nov 15;45(5):1093-1107. doi: 10.1016/j.immuni.2016.10.001. Epub 2016 Oct 25.

Abstract

Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection.

Keywords: Innate immune response; Malaria infection; Plasmacytoid dendritic cells; Type I IFN signaling.

Publication types

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

MeSH terms

  • Adaptive Immunity / immunology*
  • Animals
  • Dendritic Cells / immunology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Gene Knockdown Techniques
  • Interferon Type I / immunology*
  • Malaria / immunology*
  • Mice
  • Mice, Knockout
  • Plasmodium yoelii
  • Polymerase Chain Reaction
  • Signal Transduction / immunology*

Substances

  • Interferon Type I