Single-cell transcriptome reveals the novel role of T-bet in suppressing the immature NK gene signature.

Journal: eLife
PMID: 32406817

Abstract

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 Akt-FoxO1 axis, we further characterized the T-bet-deficient NK cells and found an augmented immature transcriptomic signature. Moreover, deletion of restores the expression of T-bet and corrects the abnormal expression of immature NK genes. Collectively, our study reveals a novel role for mTORC2-Akt-FoxO1-T-bet axis in suppressing the transcriptional signature of immature NK cells.

Authors

  • Chao Yang
    Translational Institute for Cancer Pain, Chongming Hospital Affiliated to Shanghai University of Health & Medicine Sciences (Xinhua Hospital Chongming Branch), Shanghai 202155, P. R. China.
  • Jason R Siebert
    Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Robert Burns
    Bioinfomatics Core, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Yongwei Zheng
    Laboratory of B-Cell Lymphopoiesis, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Ao Mei
    Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Benedetta Bonacci
    Flow Cytometry Core, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Demin Wang
    Laboratory of B-Cell Lymphopoiesis, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Raul A Urrutia
    Department of Surgery, Medical College of Wisconsin, Milwaukee, United States.
  • Matthew J Riese
    Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, United States.
  • Sridhar Rao
    Laboratory of Stem Cell Transcriptional Regulation, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Karen-Sue Carlson
    Department of Medicine, Medical College of Wisconsin, Milwaukee, United States.
  • Monica S Thakar
    Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
  • Subramaniam Malarkannan
    Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.

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