Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence

Abstract Vps34 is the unique member of the class III phosphoinositide 3‐kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34^fl/fl/CD122^Cre/+) is generated, deleting Vps34 during and after NK‐cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL‐15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL‐15. In mice lacking Vps34 at the terminal stage of NK‐cell development (Vps34^fl/fl/Ncr1^Cre/+), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34‐mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34‐mediated autophagy can delay NK cell senescence.