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

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 determ...

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Autores principales:	Michael C Kiritsy, Katelyn McCann, Daniel Mott, Steven M Holland, Samuel M Behar, Christopher M Sassetti, Andrew J Olive
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	IFN gamma APC function complex I PD-L1 regulation mitochondrial respiration immunometabolism Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fad7299fdf484cf5967a11a43468f79a
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spelling	oai:doaj.org-article:fad7299fdf484cf5967a11a43468f79a2021-11-17T09:45:42ZMitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells10.7554/eLife.651092050-084Xe65109https://doaj.org/article/fad7299fdf484cf5967a11a43468f79a2021-11-01T00:00:00Zhttps://elifesciences.org/articles/65109https://doaj.org/toc/2050-084XThe 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.Michael C KiritsyKatelyn McCannDaniel MottSteven M HollandSamuel M BeharChristopher M SassettiAndrew J OliveeLife Sciences Publications LtdarticleIFN gammaAPC functioncomplex IPD-L1 regulationmitochondrial respirationimmunometabolismMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IFN gamma APC function complex I PD-L1 regulation mitochondrial respiration immunometabolism Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	IFN gamma APC function complex I PD-L1 regulation mitochondrial respiration immunometabolism Medicine R Science Q Biology (General) QH301-705.5 Michael C Kiritsy Katelyn McCann Daniel Mott Steven M Holland Samuel M Behar Christopher M Sassetti Andrew J Olive Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
description	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.
format	article
author	Michael C Kiritsy Katelyn McCann Daniel Mott Steven M Holland Samuel M Behar Christopher M Sassetti Andrew J Olive
author_facet	Michael C Kiritsy Katelyn McCann Daniel Mott Steven M Holland Samuel M Behar Christopher M Sassetti Andrew J Olive
author_sort	Michael C Kiritsy
title	Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
title_short	Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
title_full	Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
title_fullStr	Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
title_full_unstemmed	Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
title_sort	mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/fad7299fdf484cf5967a11a43468f79a
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Mitochondrial respiration contributes to the interferon gamma response in antigen-presenting cells

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