TY - JOUR T1 - ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity JF - bioRxiv DO - 10.1101/247668 SP - 247668 AU - Michael J. Moore AU - Nathalie E. Blachere AU - John J. Fak AU - Christopher Y. Park AU - Kirsty Sawicka AU - Salina Parveen AU - Ilana Zucker-Scharff AU - Bruno Moltedo AU - Alexander Y. Rudensky AU - Robert B. Darnell Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/01/14/247668.abstract N2 - 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. ER -