Stage-specific requirement of kinase PDK1 for NK cells development and activation

Phosphoinositide-dependent kinase-1 (PDK1) is an important enzyme for immune cell development by connecting PI3K to downstream mTOR signaling. It is needed to investigate how PDK1 spatiotemporally orchestrates NK cells development and whether this kinase is required for NK cells effector function. In this study, we used three genetic models to delete pdk1 at respective developmental stages, including hematopoietic stem cells (Vav1-Cre used), NK cell progenitor (NKp, CD122-Cre used) and terminal NK cells (Ncr1-Cre used). We found that CD122-Cre mediated deletion of pdk1 caused a severe loss of NK cells to an extent comparable to that of deletion by Vav1-Cre, and further revealed that PDK1 was necessary for NK cells master transcription factor E4BP4 expression at the NKp stage. Moreover, Ncr1-Cre-mediated inactivation of pdk1 delayed NK cells terminal differentiation. These PDK1-deficient NK cells secreted decreased amounts of the cytokine IFN-γ, likely due to impaired downstream mTOR activation. They also exhibited reduced degranulation in response to tumor cells. Mechanistically, PDK1 was critical for the formation of NK-target conjugates and lytic synapses. Therefore, we clarify the stage-specific roles of the metabolic regulator PDK1 in NK cells biology.