Induced CD8α identifies human NK cells with enhanced proliferative fitness and modulates NK cell activation

• Published in: The Journal of clinical investigation Vol. 134; no. 15; pp. 1 - 17
• Main Authors: Cubitt, Celia C, Wong, Pamela, Dorando, Hannah K, Foltz, Jennifer A, Tran, Jennifer, Marsala, Lynne, Marin, Nancy D, Foster, Mark, Schappe, Timothy, Fatima, Hijab, Becker-Hapak, Michelle, Zhou, Alice Y, Hwang, Kimberly, Jacobs, Miriam T, Russler-Germain, David A, Mace, Emily M, Berrien-Elliott, Melissa M, Payton, Jacqueline E, Fehniger, Todd A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2024
• Subjects: Animals; Apoptosis; Biology; CD8 Antigens - genetics; CD8 Antigens - immunology; CD8 Antigens - metabolism; Cell activation; Cell culture; Cell Proliferation; Cell surface; CRISPR; Cytokines; Cytotoxicity; Humans; Interleukin 15; Interleukin-15 - genetics; Interleukin-15 - immunology; Interleukin-15 - metabolism; Killer cell immunoglobulin-like receptors; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Kinases; Leukemia; Lymphocyte Activation; Metabolism; Mice; Natural killer cells; Receptor mechanisms; Runx3 protein; T cell receptors; Tumors; Innate immunity; NK cells; Immunology; Cancer
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI173602

The surface receptor CD8α is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8α expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8α may affect critical NK cell functions. Here, we discovered that CD8α- NK cells had improved control of leukemia in xenograft models compared with CD8α+ NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8α expression was induced on approximately 30% of previously CD8α- NK cells following IL-15 stimulation. These induced CD8α+ (iCD8α+) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity compared with those that sustained existing CD8α expression (sustained CD8α+) or those that remained CD8α- (persistent CD8α-). These iCD8α+ cells originated from an IL-15Rβhi NK cell population, with CD8α 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, CD8α 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.