MiR-15/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival

Abstract

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 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, 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 indicate that these effects are mediated through the direct inhibition of an extensive network of known and novel target genes within pathways critical to cell cycle, survival, and memory. This study highlights the important role that miRNAs play in shaping the global gene expression program that is required for T cell cycle, survival, and the proper formation of memory cells.