A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation
- University of Massachusetts Medical School, United States
- Michigan State University, United States
Abstract
Cytokine-mediated activation of host immunity is central to the control of pathogens. Interferon-gamma (IFNγ) is a key cytokine in protective immunity that induces major histocompatibility complex class II molecules (MHCII) to amplify CD4+ T cell activation and effector function. Despite its central role, the dynamic regulation of IFNg-induced MHCII is not well understood. Using a genome-wide CRISPR-Cas9 screen in murine macrophages we identified genes that control MHCII surface expression. Mechanistic studies uncovered two parallel pathways of IFNg-mediated MHCII control that require the multifunctional glycogen synthase kinase 3 beta (GSK3β) or the mediator complex subunit MED16. Both pathways control distinct aspects of the IFNg response and are necessary for IFNg-mediated induction of the MHCII transactivator Ciita, MHCII expression, and CD4+ T cell activation. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4+ T cell responses.
Data availability
Raw sequencing data in FASTQ and processed formats is available for download from NCBI Gene Expression Omnibus (GEO) under accession number GSE162463 (CRISPR Screen) and GSE162464 (RNA sequencing).
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Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cellsNCBI Gene Expression Omnibus, GSE162463.
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A genetic screen in macrophages identifies new regulators of IFNg-inducible MHCII that contribute to T cell activationNCBI Gene Expression Omnibus, GSE162464.
Article and author information
Author details
Funding
National Institutes of Health (AI146504)
- Andrew J Olive
U.S. Department of Agriculture (NIFA HATCH 1019371)
- Andrew J Olive
National Institutes of Health (AI132130)
- Michael C Kiritsy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
Copyright
© 2021, Kiritsy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation
eLife 10:e65110.
https://doi.org/10.7554/eLife.65110
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