Single-cell transcriptome reveals the novel role of T-bet in suppressing the immature NK gene signature. Elife 2020 May 14;9
Date
05/15/2020Pubmed ID
32406817Pubmed Central ID
PMC7255804DOI
10.7554/eLife.51339Scopus ID
2-s2.0-85085630468 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
The transcriptional activation and repression during NK cell ontology are poorly understood. Here, using single-cell RNA-sequencing, we reveal a novel role for T-bet in suppressing the immature gene signature during murine NK cell development. Based on transcriptome, we identified five distinct NK cell clusters and define their relative developmental maturity in the bone marrow. Transcriptome-based machine-learning classifiers revealed that half of the mTORC2-deficient NK cells belongs to the least mature NK cluster. Mechanistically, loss of mTORC2 results in an increased expression of signature genes representing immature NK cells. Since mTORC2 regulates the expression of T-bet through AktS473-FoxO1 axis, we further characterized the T-bet-deficient NK cells and found an augmented immature transcriptomic signature. Moreover, deletion of Foxo1 restores the expression of T-bet and corrects the abnormal expression of immature NK genes. Collectively, our study reveals a novel role for mTORC2-AktS473-FoxO1-T-bet axis in suppressing the transcriptional signature of immature NK cells.
Author List
Yang C, Siebert JR, Burns R, Zheng Y, Mei A, Bonacci B, Wang D, Urrutia RA, Riese MJ, Rao S, Carlson KS, Thakar MS, Malarkannan SAuthors
Karen-Sue B. Carlson MD, PhD Associate Professor in the Medicine department at Medical College of WisconsinSubramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBone Marrow Cells
Cluster Analysis
Forkhead Box Protein O1
Gene Expression Profiling
Gene Expression Regulation
Genotype
Killer Cells, Natural
Machine Learning
Mechanistic Target of Rapamycin Complex 2
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Proto-Oncogene Proteins c-akt
Rapamycin-Insensitive Companion of mTOR Protein
Regulatory-Associated Protein of mTOR
Single-Cell Analysis
T-Box Domain Proteins
Transcriptome
