Kiritsy, Michael CAnkley, Laurisa MTrombley, JustinHuizinga, Gabrielle PLord, Audrey EOrning, PontusElling, RolandFitzgerald, Katherine AOlive, Andrew J2023-03-142023-03-142021-11-08Kiritsy MC, Ankley LM, Trombley J, Huizinga GP, Lord AE, Orning P, Elling R, Fitzgerald KA, Olive AJ. A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation. Elife. 2021 Nov 8;10:e65110. doi: 10.7554/eLife.65110. PMID: 34747695; PMCID: PMC8598162.2050-084X10.7554/eLife.6511034747695https://hdl.handle.net/20.500.14038/51812Cytokine-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 IFNγ-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 IFNγ-mediated MHCII control that require the multifunctional glycogen synthase kinase three beta (GSK3β) or the mediator complex subunit 16 (MED16). Both pathways control distinct aspects of the IFNγ response and are necessary for IFNγ-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.enCopyright Kiritsy et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.; Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/CD4+ T cell activationIFN-gammaMHCII expressionimmunologyinflammationmacrophagesmouseJournal ArticleeLife