ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity
- The Rockefeller University, United States
- 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
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ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunityPublicly available at the NCBI Gene Expression Omnibus (accession no:GSE96076).
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Reconstruction of the dynamic regulatory network that controls Th17 cell differentiation by systematic perturbation in primary cellsPublicly available at the NCBI Gene Expression Omnibus (accession no:GSE43955).
Article and author information
Author details
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.
Reviewing Editor
- Douglas L Black, University of California, Los Angeles, United States
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
Version history
- Received: October 26, 2017
- Accepted: May 26, 2018
- Accepted Manuscript published: May 31, 2018 (version 1)
- 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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ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity
eLife 7:e33057.
https://doi.org/10.7554/eLife.33057
