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

doi:10.1016/j.celrep.2019.07.064

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

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

Authors

John D Gagnon¹, Robin Kageyama¹, Hesham M Shehata², Marlys S Fassett³, Darryl J Mar⁴, Eric J Wigton¹, Kristina Johansson⁴, Adam J Litterman⁴, Pamela Odorizzi⁵, Dimitre Simeonov⁶, Brian J Laidlaw⁷, Marisella Panduro⁴, Sana Patel⁴, Lukas T Jeker⁸, Margaret E Feeney⁵, Michael T McManus⁹, Alexander Marson¹⁰, Mehrdad Matloubian⁵, Shomyseh Sanjabi¹¹, K Mark Ansel¹²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antigens / metabolism
Cell Cycle* / genetics
Cell Differentiation* / genetics
Cell Survival / genetics
Gene Expression Regulation
Gene Regulatory Networks
Genetic Loci
Immunologic Memory*
Lymphocytic choriomeningitis virus / physiology
Mice, Transgenic
MicroRNAs / genetics
MicroRNAs / metabolism*
T-Lymphocytes / cytology*
T-Lymphocytes / immunology*

Substances

Antigens
MicroRNAs
Mirn15 microRNA, mouse
Mirn16 microRNA, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding