0      0

Innate Immunity: Mechanisms and Modulation | EK39


EK39-eposter-ankley-laurisa - Med16 and GSK3b are independently required for MHCII expression and CD4+ T cell activation ex vivo


Apr 12, 2021 12:00am ‐ Apr 12, 2021 12:00am

Description

Med16 and GSK3b are independently required for MHCII expression and CD4+ T cell activation ex vivo Laurisa Ankley1*, Michael Kiritsy2, Gabrielle Huizinga1, Justin Trombley1, Andrew Olive1,2 1Department of Microbiology and Molecular Genetics, Michigan State University; 2Department of Microbiology and Physiological Systems, University of Massachusetts Medical School The IFNg-dependent induction of MHCII expression is critical for CD4+ T cell function. Dysregulation of MHCII is associated with autoimmunity, graft versus host disease, and increased susceptibility to cancers and chronic infections. Despite its central role in host immunity, the complex and dynamic regulation of IFNg-induced MHCII is poorly understood. We hypothesize that modulating MHCII regulatory pathways in macrophages will directly alter T cell effector function. Our goal is to dissect MHCII regulation to identify new therapeutic targets that will improve MHCII disease states, antigen presentation, and host immune responses against persistent infections. Using a CRISPR screen we identified new MHCII regulators including the multifunctional kinase GSK3 and the mediator complex subunit Med16. Mechanistic studies found that both GSK3 and Med16 are essential for IFNg-mediated Ciita induction and for macrophages to serve as antigen presenting cells for CD4+ T cells. Using the GSK3 inhibitor, CHIR99021, in Med16 KO macrophages we observed further inhibition of MHCII expression suggesting GSK3 and Med16 function in parallel networks. To test this directly, RNAseq was used to globally profile the transcriptomes in Med16 and GSK3 KO cells in the presence and absence of IFNg. We found that Med16 and GSK3 control distinct transcriptional networks without disrupting canonical IFNg transcription factors like Stat1, Stat3 and IRF1. The RNAseq also suggested IFNg dependent control of cytokines are disrupted in the absence of GSK3 and Med16 which we confirmed using Mycobacterium tuberculosis infection. Thus, GSK3 and Med16 are parallel regulators that balance IFNg responses in macrophages and modulate adaptive immune responses.

Speaker(s):

You must be logged in and own this session in order to post comments.

Print Certificate
Completed on: token-completed_on
Print Transcript
Please select the appropriate credit type:
/
test_id: 
credits: 
completed on: 
rendered in: 
* - Indicates answer is required.
token-content

token-speaker-name
token-index
token-content
token-index
token-content
token-index
token-content
token-index
token-content
token-index
token-content
token-index
token-content
/
/
token-index
token-content
token-index
token-content