ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity

  1. Michael J Moore
  2. Nathalie E Blachere
  3. John J Fak
  4. Christopher Y Park
  5. Kirsty Sawicka
  6. Salina Parveen
  7. Ilana Zucker-Scharff
  8. Bruno Moltedo
  9. Alexander Y Rudensky
  10. Robert B Darnell  Is a corresponding author
  1. The Rockefeller University, United States
  2. Memorial Sloan Kettering Cancer Center, United States

Abstract

Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in mouse T cells, revealing unanticipated actions in regulating T cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through novel AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T cell activation kinetics cell autonomously, by attenuating activation marker expression, limiting T cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T cell responses to acute viral infection and enhanced anti-viral immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T cell expansion and effector functions, and suggest ZFP36 inhibition as a strategy to enhance immune-based therapies.

Data availability

Sequencing data are in GEO under the accession code GSE96076

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Michael J Moore

    Laboratory of Molecular Neuro-Onology, The Rockefeller University, New York, United States
    Competing interests
    Michael J Moore, currently affiliated with Regeneron Phrmaceuticals. The author has no other financial competing interests to declare.
  2. Nathalie E Blachere

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  3. John J Fak

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  4. Christopher Y Park

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  5. Kirsty Sawicka

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  6. Salina Parveen

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  7. Ilana Zucker-Scharff

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  8. Bruno Moltedo

    The Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Alexander Y Rudensky

    The Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  10. Robert B Darnell

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    For correspondence
    darnelr@rockefeller.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5134-8088

Funding

National Institutes of Health

  • Robert B Darnell

Starr Foundation

  • Robert B Darnell

Jane Coffin Childs Memorial Fund for Medical Research

  • Michael J Moore

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse strains were maintained at the University of California, San Francisco (UCSF) specific pathogen-free animal facility under protocol number AN110094. All animal protocols were approved by and in accordance with the guidelines established by the Institutional Animal Care and Use Committee and Laboratory Animal Resource Center

Reviewing Editor

  1. Douglas L Black, University of California, Los Angeles, United States

Publication history

  1. Received: October 26, 2017
  2. Accepted: May 26, 2018
  3. Accepted Manuscript published: May 31, 2018 (version 1)
  4. Version of Record published: July 5, 2018 (version 2)

Copyright

© 2018, Moore 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. Michael J Moore
  2. Nathalie E Blachere
  3. John J Fak
  4. Christopher Y Park
  5. Kirsty Sawicka
  6. Salina Parveen
  7. Ilana Zucker-Scharff
  8. Bruno Moltedo
  9. Alexander Y Rudensky
  10. Robert B Darnell
(2018)
ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity
eLife 7:e33057.
https://doi.org/10.7554/eLife.33057

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