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Significance Adoptive transfer of allogeneic natural killer (NK) cells into leukemia patients can lead to remission; however, therapies are hindered by inefficient expansion and limited persistence of these lymphocytes. We now report that Kruppel-like factor 2 (KLF2) regulates both NK cell proliferation and survival. KLF2 limits homeostatic expansion of NK cells in a cell-intrinsic manner. In addition, KLF2 instructs mature NK cells to home to IL-15–rich niches, which is necessary for continued survival under homeostatic conditions. Therefore, targeting KLF2 while providing rate-limiting survival factors such as transpresented IL-15 may improve NK cell engraftment and sustainability in cancer patients.

Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival