miR-15/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival
John D. Gagnon,
Robin Kageyama,
Hesham M. Shehata,
Marlys S. Fassett,
Darryl J. Mar,
Eric J. Wigton,
Kristina Johansson,
Adam J. Litterman,
Pamela Odorizzi,
Dimitre Simeonov,
Brian J. Laidlaw,
Marisella Panduro,
Sana Patel,
Lukas T. Jeker,
Margaret E. Feeney,
Michael T. McManus,
Alexander Marson,
Mehrdad Matloubian,
Shomyseh Sanjabi,
K. Mark Ansel
Affiliations
John D. Gagnon
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
Robin Kageyama
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
Hesham M. Shehata
Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158, USA
Marlys S. Fassett
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
Darryl J. Mar
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
Eric J. Wigton
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
Kristina Johansson
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
Adam J. Litterman
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
Pamela Odorizzi
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Dimitre Simeonov
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
Brian J. Laidlaw
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
Marisella Panduro
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
Sana Patel
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
Lukas T. Jeker
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
Margaret E. Feeney
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Michael T. McManus
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
Alexander Marson
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
Mehrdad Matloubian
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Shomyseh Sanjabi
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
K. Mark Ansel
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; Corresponding author
Summary: 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. : 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. Keywords: microRNA, miRNA, miR-16, miR-15a, miR-15b, IL-7 receptor, CD127, Argonaute HITS-CLIP, cell cycle, T cell memory
