Chronic NK cell activation results in a dysfunctional, tissue resident–like state mediated by KLF2 deficiency Available to Purchase

• Chronic NK cell activation with interleukin-15 and activating receptors induces divergent molecular signatures, weakening cytotoxicity.

• Modulating NK cell KLF2 expression provides resistance to activation-induced dysfunction and alters chemotaxis and homing to the bone marrow.

Adoptive transfer of natural killer (NK) cells can induce complete remissions in 30% to 50% of patients with refractory acute myeloid leukemia and lymphoma. Although blood chimerism occurs, attaining functional homing to the site of tumor without exhaustion has been elusive. During chronic infections and tumorigenesis, exposure to activating stimuli weakens the effector activity of NK cells. Despite this knowledge, there is little known about the mechanisms that govern this dysregulation and whether these disparate activating stimuli use distinct pathways to downregulate effector immunity. In this study, we reveal that chronic NK cell activation receptor (NKAR) stimulation and chronic interleukin-15 exposure impart distinct modes of dysregulation, with NKAR stimulation inducing a tissue resident–like state that resembles that of tumor-infiltrating NK cells in patients with cancer. Using loss- and gain-of-function studies, we identify the transcription factor KLF2 as a master regulator of the NK cell response to chronic activation and provide evidence that KLF2 overexpression promotes NK cell cytotoxicity, cytokine production, and chemotaxis and inhibits the development of dysfunctional, tissue resident–like features. Using KLF2 reporter mice, we show that in certain tissues, tissue resident NK cells are predominantly KLF2^–, whereas circulating NK cells in these tissues are overwhelmingly KLF2⁺. Lastly, using mixed bone marrow chimeras, we demonstrate that conditional KLF2 deficiency in NK cells leads to altered homing and the acquisition of tissue resident–like features in vivo. Together, these findings highlight the profound changes NK cells undergo during prolonged activation and advance our understanding of how some NK cell therapies fail during malignant relapse.