Coordinate control of T cell proliferation survival and differentiation are essential for host protection from pathogens and cancer Long-lived memory cells whose precursors are formed during the initial immunological insult provide protection from future encounters and their generation is the goal of many vaccination strategies microRNAs miRNAs are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes Here using compound conditional mutant mice to eliminate miR-15 16 family miRNAs in T cells we show that miR-15 16 restrict T cell cycle survival and memory T cell differentiation High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15 16-deficient T cells indicates that these effects are mediated through the direct inhibition of an extensive network of target genes within pathways critical to cell cycle survival and memory Copyright 2019 The Author s Published by Elsevier Inc All rights reserved