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dc.contributor.authorKiritsy, Michael C.
dc.contributor.authorMott, Daniel
dc.contributor.authorBehar, Samuel M.
dc.contributor.authorSassetti, Christopher M.
dc.contributor.authorOlive, Andrew J.
dc.date2022-08-11T08:08:25.000
dc.date.accessioned2022-08-23T15:54:48Z
dc.date.available2022-08-23T15:54:48Z
dc.date.issued2020-11-23
dc.date.submitted2020-12-09
dc.identifier.citation<p>bioRxiv 2020.11.22.393538; doi: https://doi.org/10.1101/2020.11.22.393538. <a href="https://doi.org/10.1101/2020.11.22.393538" target="_blank">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2020.11.22.393538
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29623
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review</p>
dc.description.abstractThe 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 toll-like receptor ligation relies 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 macrophages to identify the regulators of IFNγ-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 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.
dc.language.isoen_US
dc.relationNow published in eLife doi: 10.7554/eLife.65109
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nd/4.0/
dc.subjectImmunology
dc.subjectantigen presenting cells
dc.subjectimmune response
dc.subjectinnate immunity
dc.subjectImmunity
dc.subjectImmunology of Infectious Disease
dc.subjectImmunopathology
dc.titleMitochondrial respiration contributes to the interferon gamma response in antigen presenting cells [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2869&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1840
dc.identifier.contextkey20497515
refterms.dateFOA2022-08-23T15:54:48Z
html.description.abstract<p><p id="x-x-x-p-2">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 toll-like receptor ligation relies 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 macrophages to identify the regulators of IFNγ-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 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.</p>
dc.identifier.submissionpathfaculty_pubs/1840
dc.contributor.departmentDepartment of Microbiology and Physiological Systems


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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