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

By Michael J Moore, Nathalie E Blachere, John J Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-Scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. Darnell

Posted 14 Jan 2018
bioRxiv DOI: 10.1101/247668 (published DOI: 10.7554/elife.33057)

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 T-cells, which revealed 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 a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics in a cell autonomous manner, 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 novel strategy to enhance immune-based therapies.

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