University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Microbiology and Physiological Systems; Department of Medicine, Division of Infectious Diseases and Immunology
Publication Date
2020-08-12
Document Type
Article Preprint
Disciplines
Immunology and Infectious Disease
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.
Keywords
Immunology, cytokines, immunity, genomics
Rights and Permissions
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.
DOI of Published Version
10.1101/2020.08.12.248252
Source
bioRxiv 2020.08.12.248252; doi: https://doi.org/10.1101/2020.08.12.248252. Link to preprint on bioRxiv service.
Journal/Book/Conference Title
bioRxiv
Repository Citation
Kiritsy MC, Michigan State University, Michigan State University, Michigan State University, Lord AE, Orning MA, Elling R, Fitzgerald KA, Michigan State University. (2020). A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.08.12.248252. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1773
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.