mTORC1 and mTORC2 differentially promote natural killer cell development.

Abstract

Natural killer (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. <i>Ncr1^iCre</i>-mediated deletion of <i>Rptor</i> or <i>Rictor</i> 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 <i>Rptor</i> cKO mice, while, the terminal maturation from the CD27⁺CD11b⁺ to the CD27^-CD11b⁺ stage is compromised in <i>Rictor</i> 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.