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Cell Rep. 2019 Aug 20;28(8):2169-2181.e4. doi: 10.1016/j.celrep.2019.07.064.

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

Author information

1
Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA.
3
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
8
Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
9
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
10
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
11
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA.
12
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mark.ansel@ucsf.edu.

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 (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.

KEYWORDS:

Argonaute HITS-CLIP; CD127; IL-7 receptor; T cell memory; cell cycle; miR-15a; miR-15b; miR-16; miRNA; microRNA

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