A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation [preprint]
Authors
Kiritsy, Michael C.Ankley, Laurisa M
Trombley, Justin
Huizinga, Gabrielle P
Lord, Audrey E.
Orning, Pontus
Elling, Roland
Fitzgerald, Katherine A.
Olive, Andrew J.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDepartment of Microbiology and Physiological Systems
Document Type
PreprintPublication Date
2020-08-12
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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.Source
bioRxiv 2020.08.12.248252; doi: https://doi.org/10.1101/2020.08.12.248252. Link to preprint on bioRxiv service.
DOI
10.1101/2020.08.12.248252Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29552Related Resources
Now published in eLife doi: 10.7554/eLife.65110Rights
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2020.08.12.248252
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Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.