Robust T cell activation requires an eIF3-driven burst in T cell receptor translation
Abstract
Activation of T cells requires a rapid surge in cellular protein synthesis. However, the role of translation initiation in the early induction of specific genes remains unclear. Here we show human translation initiation factor eIF3 interacts with select immune system related mRNAs including those encoding the T cell receptor (TCR) subunits TCRA and TCRB. Binding of eIF3 to the TCRA and TCRB mRNA 3'-untranslated regions (3'-UTRs) depends on CD28 coreceptor signaling and regulates a burst in TCR translation required for robust T cell activation. Use of the TCRA or TCRB 3'-UTRs to control expression of an anti-CD19 chimeric antigen receptor (CAR) improves the ability of CAR-T cells to kill tumor cells in vitro. These results identify a new mechanism of eIF3-mediated translation control that can aid T cell engineering for immunotherapy applications.
Data availability
Sequencing data has been deposited in GEO (GSE191306).Code used to analyze the microscopy images is available on github at https://github.com/Llamero/TCR_colocalization_analysis-macro
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Genome-wide mapping of eIF3-RNA interactions in Jurkat cells using PAR-CLIPNCBI Gene Expression Omnibus, GSE191306.
Article and author information
Author details
Funding
National Institutes of Health (R01-GM065050)
- Dasmanthie DeSilva
- Grant H Chin
- Jamie HD Cate
Cancer Research Institute (N/A)
- Alexander Marson
Chan Zuckerberg Initiative (N/A)
- Ryan A Apathy
- Theodore L Roth
- Alexander Marson
Innovative Genomics Institute (N/A)
- Ryan A Apathy
- Theodore L Roth
- Alexander Marson
Parker Institute for Cancer Immunotherapy (N/A)
- Alexander Marson
Tang Prize for Biopharmaceutical Science (N/A)
- Jamie HD Cate
Damon Runyon Cancer Research Foundation (DRR#37-15)
- Nicholas T Ingolia
National Institutes of Health (DP2 CA195768)
- Lucas Ferguson
- Marek Kudla
- Nicholas T Ingolia
National Institutes of Health (P30EY003176)
- Benjamin E Smith
National Institutes of Health (S10 OD018174)
- Dasmanthie DeSilva
Care-for-Rare Foundation (N/A)
- Franziska Blaeschke
German Research Foundation (N/A)
- Franziska Blaeschke
Burroughs Wellcome Fund (N/A)
- Alexander Marson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, France
Version history
- Received: September 28, 2021
- Preprint posted: October 4, 2021 (view preprint)
- Accepted: December 30, 2021
- Accepted Manuscript published: December 31, 2021 (version 1)
- Version of Record published: January 13, 2022 (version 2)
Copyright
© 2021, DeSilva et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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