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

Antigen presenting cells (APC) act as an integration point where signaling and metabolic pathways collaboratively determine cellular activation state and shape T cell responses. We performed a series of genome-wide knockout screens in interferon gamma (IFNg)-stimulated macrophages, identifying overlapping sets of regulators that control the expression of the T cell stimulatory or inhibitory proteins, MHCII, CD40, and PD-L1. This multi-screen approach defined novel pathways that differentially control these functionally-distinct proteins, and identified mitochondrial function as a global regulator of the IFNg response. Specifically, we report that complex I of the mitochondrial respiratory chain is necessary for signal transduction via the IFNgreceptor, and consequently for both macrophages and dendritic cells to function as APCs. The importance of mitochondrial function for the IFNg response contrasts with the known glycolytic dependency of pattern-recognition receptor stimulation, implicating metabolic state as a fulcrum of innate immunity. Genome-wide CRISPR knockout screen in murine macrophages for regulators of interferon gamma induced MHCII, CD40 or PD-L1