1. Cell Biology
  2. Immunology and Inflammation

Robust T cell activation requires an eIF3-driven burst in T cell receptor translation

  1. Dasmanthie DeSilva
  2. Lucas Ferguson
  3. Grant H Chin
  4. Benjamin E Smith
  5. Ryan A Apathy
  6. Theodore L Roth
  7. Franziska Blaeschke
  8. Marek Kudla
  9. Alexander Marson
  10. Nicholas T Ingolia
  11. Jamie HD Cate  Is a corresponding author
  1. University of California, Berkeley, United States
  2. University of California, San Francisco, United States
  3. Gladstone-UCSF Institute of Genomic Immunology, United States
https://doi.org/10.7554/eLife.74272
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  1. Dasmanthie DeSilva
  2. Lucas Ferguson
  3. Grant H Chin
  4. Benjamin E Smith
  5. Ryan A Apathy
  6. Theodore L Roth
  7. Franziska Blaeschke
  8. Marek Kudla
  9. Alexander Marson
  10. Nicholas T Ingolia
  11. Jamie HD Cate
(2021)
Robust T cell activation requires an eIF3-driven burst in T cell receptor translation
eLife 10:e74272.
https://doi.org/10.7554/eLife.74272
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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

The following data sets were generated

Article and author information

Author details

  1. Dasmanthie DeSilva

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    Dasmanthie DeSilva, A provisional patent application has been filed on some of the work presented herein..

  2. Lucas Ferguson

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  3. Grant H Chin

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  4. Benjamin E Smith

    School of Optometry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  5. Ryan A Apathy

    Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  6. Theodore L Roth

    Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    Theodore L Roth, is a co-founder of Arsenal Therapeutics..

  7. Franziska Blaeschke

    Gladstone-UCSF Institute of Genomic Immunology, San Francisco, United States
    Competing interests
    No competing interests declared.

  8. Marek Kudla

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.

  9. Alexander Marson

    Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, United States
    Competing interests
    Alexander Marson, is a compensated co-founder, member of the boards of directors, and a member of the scientific advisory boards of Spotlight Therapeutics and Arsenal Biosciences. Was a compensated member of the scientific advisory board at PACT Pharma and was a compensated advisor to Juno Therapeutics. Owns stock in Arsenal Biosciences, Spotlight Therapeutics, PACT Pharma and Merck. A.M. has received fees from Vertex, Merck, Amgen, Trizell, Genentech, AlphaSights, Rupert Case Management and Bernstein. Is an investor in and informal advisor to Offline Ventures. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem..

  10. Nicholas T Ingolia

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3395-1545

  11. Jamie HD Cate

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    j-h-doudna-cate@berkeley.edu
    Competing interests
    Jamie HD Cate, A provisional patent application has been filed on some of the work presented herein..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5965-7902

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

  1. Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, France

Publication history

  1. Received: September 28, 2021
  2. Preprint posted: October 4, 2021 (view preprint)
  3. Accepted: December 30, 2021
  4. Accepted Manuscript published: December 31, 2021 (version 1)
  5. 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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  1. Dasmanthie DeSilva
  2. Lucas Ferguson
  3. Grant H Chin
  4. Benjamin E Smith
  5. Ryan A Apathy
  6. Theodore L Roth
  7. Franziska Blaeschke
  8. Marek Kudla
  9. Alexander Marson
  10. Nicholas T Ingolia
  11. Jamie HD Cate
(2021)
Robust T cell activation requires an eIF3-driven burst in T cell receptor translation
eLife 10:e74272.
https://doi.org/10.7554/eLife.74272

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