T-bet-dependent ILC1- and NK cell-derived IFN-γ mediates cDC1-dependent host resistance against Toxoplasma gondii

PLoS Pathog. 2021 Jan 19;17(1):e1008299. doi: 10.1371/journal.ppat.1008299. eCollection 2021 Jan.

Abstract

Host resistance against intracellular pathogens requires a rapid IFN-γ mediated immune response. We reveal that T-bet-dependent production of IFN-γ is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii. A detailed analysis of the cellular sources for T-bet-dependent IFN-γ identified that ILC1s and to a lesser degree NK, but not TH1 cells, were involved in the regulation of inflammatory DCs via IFN-γ. Mechanistically, we established that T-bet dependent innate IFN-γ is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T. gondii infection. Our data identifies that T-bet dependent production of IFN-γ by ILC1 and NK cells is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection.

Publication types

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

MeSH terms

  • Animals
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / microbiology
  • Female
  • Immunity, Innate / immunology*
  • Interferon Regulatory Factors / physiology
  • Interferon-gamma / metabolism*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / microbiology
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Lymphocytes / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Toxoplasma / immunology*
  • Toxoplasma / metabolism
  • Toxoplasmosis / immunology*
  • Toxoplasmosis / metabolism
  • Toxoplasmosis / microbiology

Substances

  • Interferon Regulatory Factors
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • interferon regulatory factor-8
  • Interferon-gamma