Uhrf1 Controls iNKT Cell Survival and Differentiation through the Akt-mTOR Axis

•Uhrf1 expression is upregulated at stage 1 during iNKT cell development•Loss of Uhrf1 leads to defective iNKT cell differentiation and increased apoptosis•Akt-mTOR axis is attenuated in Uhrf1-deficient stage 1 iNKT cellsActive•Akt rescues iNKT cell developmental defects in Uhrf1-deficient mice

SummaryUhrf1 (also known as Np95) is a regulator of DNA methylation and histone ubiquitination and plays an important role in embryogenesis and tumorigenesis. Here, we report that Uhrf1 is essential for invariant natural killer T (iNKT) cell development. We found that Uhrf1 was significantly upregulated in stage 1 iNKT cells. Targeted disruption of Uhrf1 resulted in stage 1-specific transition defects as observed by not only increased apoptosis, but also aberrant effector differentiation, which eventually led to the impaired generation of iNKT cells in Uhrf1-deficient mice. Notably, Uhrf1 deficiency resulted in attenuated activation of Akt-mTOR signaling in stage 1 iNKT cells and overexpression of active Akt rescued iNKT cell developmental defects. Collectively, our results suggest that Uhrf1 regulation of the Akt-mTOR signaling pathway is required for iNKT cell development.

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