{"doi":"10.1101/2020.08.12.248252","title":"A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation","abstract":"Abstract Cytokine-mediated activation of host immunity is central to the control of pathogens. A key cytokine in protective immunity is interferon-gamma (IFNγ), which is a potent activator of antimicrobial and immunomodulatory effectors within the host. A major role of IFNγ is to induce major histocompatibility complex class II molecules (MHCII) on the surface of cells, which is required for CD4 + T cell activation. Despite its central role in host immunity, the complex and dynamic regulation of IFNγ-induced MHCII is not well understood. Here, we integrated functional genomics and transcriptomics to comprehensively define the genetic control of IFNγ-mediated MHCII surface expression in macrophages. Using a genome-wide CRISPR-Cas9 library we identified genes that control MHCII surface expression, many of which have yet to be associated with MHCII. Mechanistic studies uncovered two parallel pathways of IFNγ-mediated MHCII control that require the multifunctional glycogen synthase kinase 3 beta (GSK3β) or the mediator complex subunit MED16. Both pathways are necessary for IFNγ-mediated induction of the MHCII transactivator CIITA, MHCII expression, and CD4 + T cell activation. Using transcriptomic analysis, we defined the regulons controlled by GSK3β and MED16 in the presence and absence of IFNγ and identified unique networks of the IFNγ-mediated transcriptional landscape that are controlled by each gene. Our analysis suggests GSK3β and MED16 control distinct aspects of the IFNγ-response and are critical for macrophages to respond appropriately to IFNγ. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4 + T cell responses by macrophages. These discoveries will aid in our basic understanding of macrophage-mediated immunity and will shed light on mechanisms of failed adaptive responses pervasive in infectious disease, autoimmunity, and cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127186,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":461801,"name":"Laurisa M Ankley","orcid":"0000-0002-0635-9001","position":1,"is_corresponding":false},{"id":108671,"name":"Justin D. Trombley","orcid":"0000-0002-3856-3138","position":2,"is_corresponding":false},{"id":576505,"name":"Gabrielle P Huizinga","orcid":null,"position":3,"is_corresponding":false},{"id":576506,"name":"Audrey E. Lord","orcid":null,"position":4,"is_corresponding":false},{"id":230562,"name":"Pontus Ørning","orcid":"0000-0002-6177-6916","position":5,"is_corresponding":false},{"id":575702,"name":"Roland Elling","orcid":"0000-0002-2209-4154","position":6,"is_corresponding":false},{"id":109691,"name":"Katherine A. Fitzgerald","orcid":"0000-0003-3175-609X","position":7,"is_corresponding":false},{"id":461802,"name":"Andrew J. Olive","orcid":"0000-0003-3441-3113","position":8,"is_corresponding":false},{"id":562004,"name":"Michael C Kiritsy","orcid":"0000-0001-8364-8088","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-18T23:15:30.930746Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}