scholarly journals Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation

2017 ◽  
Vol 199 (12) ◽  
pp. 4056-4065 ◽  
Author(s):  
Charles W. Tran ◽  
Samuel D. Saibil ◽  
Thierry Le Bihan ◽  
Sara R. Hamilton ◽  
Karl S. Lang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

2020 ◽  
Author(s):  
Michael C. Kiritsy ◽  
Laurisa M. Ankley ◽  
Justin D. Trombley ◽  
Gabrielle P. Huizinga ◽  
Audrey E. Lord ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Glycogen Synthase ◽  
Surface Expression ◽  
Host Immunity ◽  
Dynamic Regulation ◽  
Genome Wide ◽  
A Genome ◽  
Mhcii Expression

AbstractCytokine-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.

scholarly journals A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Michael C Kiritsy ◽  
Laurisa M Ankley ◽  
Justin Trombley ◽  
Gabrielle P Huizinga ◽  
Audrey E Lord ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Glycogen Synthase ◽  
Surface Expression ◽  
Dynamic Regulation ◽  
Cell Responses ◽  
Genome Wide ◽  
A Genome ◽  
Mhcii Expression

Cytokine-mediated activation of host immunity is central to the control of pathogens. Interferon-gamma (IFNg) 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 IFNg-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 IFNg-mediated MHCII control that require the multifunctional glycogen synthase kinase 3 beta (GSK3b) or the mediator complex subunit MED16. Both pathways control distinct aspects of the IFNg response and are necessary for IFNg-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.

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