Department of Microbiology and Physiological Systems
Immunity | Immunology of Infectious Disease | Immunopathology
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.
Immunology, antigen presenting cells, immune response, innate immunity
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DOI of Published Version
bioRxiv 2020.11.22.393538; doi: https://doi.org/10.1101/2020.11.22.393538. Link to preprint on bioRxiv.
Kiritsy MC, Mott D, Behar SM, Sassetti CM, Olive AJ. (2020). Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.11.22.393538. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1840
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