Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells
- University of Massachusetts Medical School, United States
- National Institute of Allergy and Infectious Diseases, United States
- Michigan State University, United States
Abstract
The immunological synapse allows antigen presenting cells (APC) 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 (IFNg). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNg-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. 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 IFNg signaling pathway. We report that the IFNg 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 IFNg and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.
Data availability
Raw sequencing data in FASTQ and processed formats is available for download from NCBI Gene Expression Omnibus (GEO) under accession number GSE162463.
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Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cellsNCBI Gene Expression Omnibus, GSE162463.
Article and author information
Author details
Christopher M Sassetti
Funding
National Institutes of Health (AI146504)
- Andrew J Olive
National Institutes of Health (AI132130)
- Christopher M Sassetti
U.S. Department of Defense (W81XWH2010147)
- Andrew J Olive
U.S. Department of Agriculture (NIFA HATCH 1019371)
- Andrew J Olive
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tiffany Horng, ShanghaiTech University, China
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PROTO201800057) of Michigan State University and (Protocol# 1649) of the University of Massachusetts Medical School.
Human subjects: All human blood samples were donated following informed consent and approved under IRB protocol I-375-19
Version history
- Preprint posted: November 23, 2020 (view preprint)
- Received: November 23, 2020
- Accepted: October 28, 2021
- Accepted Manuscript published: November 2, 2021 (version 1)
- Version of Record published: November 17, 2021 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells
eLife 10:e65109.
https://doi.org/10.7554/eLife.65109
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