Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis

Cell. 2023 Dec 7;186(25):5536-5553.e22. doi: 10.1016/j.cell.2023.11.002. Epub 2023 Nov 28.


Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.

Keywords: Mycobacterium tuberculosis; innate immunology; interstitial macrophages; lung; mice; neutrophil extracellular traps; neutrophils; plasmacytoid dendritic cells; type I interferons.

Publication types

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

MeSH terms

  • Animals
  • Cytokines
  • Dendritic Cells
  • Humans
  • Interferon Type I*
  • Macrophages / microbiology
  • Mice
  • Neutrophils
  • Tuberculosis*


  • Interferon Type I
  • Cytokines