miR-15/16 restrain cell cycle and memory T cell accumulation

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 in future encounters and their generation is the goal of many vaccination strategies. microRNAs are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes. Here, using new compound conditional mutant mice to eliminate miR-15/16 family miRNAs in T cells, we show that miR-15/16 restrict T cell cycle and memory T cell accumulation. High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15/16 deficient T cells indicated that these effects are mediated through direct inhibition of an extensive network of known and novel target genes within pathways critical to cell cycle and memory. Gene expression analysis of miR-15/16 sufficient and miR-15/16 deficient CD4+ T cells stimulated in vitro with anti-CD3 and anti-CD28 for 3 days and rested in the presence of IL-2 (20U/ml).