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

• Published in: Cell reports (Cambridge) 2019-08, Vol.28 (8), p.2169-2181.e4
• Main Authors: Gagnon, John D., Kageyama, Robin, Shehata, Hesham M., Fassett, Marlys S., Mar, Darryl J., Wigton, Eric J., Johansson, Kristina, Litterman, Adam J., Odorizzi, Pamela, Simeonov, Dimitre, Laidlaw, Brian J., Panduro, Marisella, Patel, Sana, Jeker, Lukas T., Feeney, Margaret E., McManus, Michael T., Marson, Alexander, Matloubian, Mehrdad, Sanjabi, Shomyseh, Ansel, K. Mark
• Format: Article
• Language: English
• Subjects: Animals; Antigens - metabolism; Argonaute HITS-CLIP; CD127; cell cycle; Cell Cycle - genetics; Cell Differentiation - genetics; Cell Survival - genetics; Gene Expression Regulation; Gene Regulatory Networks; Genetic Loci; IL-7 receptor; Immunologic Memory; Lymphocytic choriomeningitis virus - physiology; Mice, Transgenic; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miR-15a; miR-15b; miR-16; miRNA; T cell memory; T-Lymphocytes - cytology; T-Lymphocytes - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.064

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. [Display omitted] •miR-15/16 and their target mRNAs are abundant in Ago2 complexes in T cells•miR-15/16 regulate the number and type of T cells generated during viral infection•miR-15/16 target acts in pathways critical for T cell expansion and differentiation Coordinate control of T cell proliferation, survival, and differentiation are essential for effective cell-mediated adaptive immunity. Gagnon et al. define roles for the miR-15/16 family of microRNAs in restricting T cell cycle and long-lived memory T cell accumulation through the direct inhibition of a very large network of target mRNAs.