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The surface receptor CD8[alpha] is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8[alpha] expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8[alpha] may affect critical NK cell functions. Here, we discovered that CD8[[alpha].sup.-] NK cells had improved control of leukemia in xenograft models compared with CD8[[alpha].sup.+] NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8[alpha] expression was induced on approximately 30% of previously CD8[[alpha].sup.- ] NK cells following IL-15 stimulation. These induced CD8[[alpha].sup.+] (iCD8[[alpha].sup.+]) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity compared with those that sustained existing CD8[alpha] expression (sustained CD8[[alpha].sup.+]) or those that remained CD8[[alpha].sup.-] (persistent CD8[alpha]). These iCD8[[alpha].sup.+] cells originated from an IL- 15R[[beta].sup.hi] NK cell population, with CD8[alpha] expression dependent on the transcription factor RUNX3. Moreover, CD8A CRISPR/Cas9 deletion resulted in enhanced responses through the activating receptor NKp30, possibly by modulating KIR inhibitory function. Thus, CD8[alpha] status identified human NK cell capacity for IL-15-induced proliferation and metabolism in a time-dependent fashion, and its presence had a suppressive effect on NK cell-activating receptors., Introduction NK cells are innate lymphoid cells that protect the host from infection and malignant transformation through direct cytotoxicity and communication via cytokine and chemokine production (1-3). Human NK cells [...]