Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells

Elife. 2021 Nov 2;10:e65109. doi: 10.7554/eLife.65109.


The immunological synapse allows antigen-presenting cells (APCs) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While pathways downstream of toll-like receptors rely on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNγ). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNγ-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multiscreen approach enabled us to identify novel pathways that preferentially control functionally distinct proteins. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNγ signaling pathway. We report that the IFNγ response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNγ and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.

Keywords: APC function; IFN gamma; PD-L1 regulation; complex I; human; immunology; immunometabolism; inflammation; mitochondrial respiration; mouse.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / physiology*
  • Cell Line
  • Cell Respiration*
  • Humans
  • Interferon-gamma / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / physiology*


  • IFNG protein, human
  • IFNG protein, mouse
  • Interferon-gamma

Associated data

  • GEO/GSE162463