Raptor and Rictor differentially promote Natural Killer cell development

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Abstract

NK cells are innate lymphoid cells that are essential for innate and adaptive immunity. Mechanistic target of rapamycin (mTOR) is critical for NK cell development; however, the independent roles of mTORC1 or mTORC2 in regulating this process remain unknown. Ncr1^iCre-mediated deletion of Rptor or Rictor in mice results in altered homeostatic NK cellularity and impaired development at distinct stages. The transition from the CD27⁺CD11b^- to the CD27⁺CD11b⁺ stage is impaired in Rptor cKO mice, while, the terminal maturation from the CD27⁺CD11b⁺ to the CD27^-CD11b⁺ stage is compromised in Rictor cKO mice. Mechanistically, Raptor-deficiency renders substantial alteration of the gene expression profile including transcription factors governing early NK cell development. Comparatively, loss of Rictor causes more restricted transcriptome changes. The reduced expression of T-bet correlates with the terminal maturation defects and results from impaired mTORC2-Akt^S473-FoxO1 signaling. Collectively, our results reveal the divergent roles of mTORC1 and mTORC2 in NK cell development.

Data availability

We have deposited the RNA-Seq data in NCBI SRA BioSample database. The SRA BioProject ID is PRJNA434424.

The following data sets were generated

1. Malarkannan S et al
(2018) RNA-Seq data from
PRJNA434424.

https://www.ncbi.nlm.nih.gov/bioproject/

Article and author information

Author details

Chao Yang

Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, United States

Competing interests
The authors declare that no competing interests exist.
Shirng-Wern Tsaih

Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, United States

Competing interests
The authors declare that no competing interests exist.
Angela Lemke

Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, United States

Competing interests
The authors declare that no competing interests exist.
Michael J Flister

Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, United States

Competing interests
The authors declare that no competing interests exist.
Monica S Thakar

Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, United States

Competing interests
The authors declare that no competing interests exist.
Subramaniam Malarkannan

Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, United States

For correspondence
Subramaniam.Malarkannan@bcw.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7511-2731

Funding

National Institute of Allergy and Infectious Diseases

Subramaniam Malarkannan

National Cancer Institute

Subramaniam Malarkannan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal protocols were approved by Institutional Animal Care and Use Committees of the IACUC at the Medical College of Wisconsin, Milwaukee, WI. Medical College of Wisconsin is formally accredited by AAALAC and all the animal care and use-protocols used in this study fully adhere to the specified guide lines of AAALAC. The unique animal protocols that are approved by the IACUC and used in this study are: AUA1500 and AUA1512.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.