| Autor: |
Cubitt CC; Division of Oncology, Siteman Cancer Center, and., Wong P; Division of Oncology, Siteman Cancer Center, and., Dorando HK; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA., Foltz JA; Division of Oncology, Siteman Cancer Center, and., Tran J; Division of Oncology, Siteman Cancer Center, and., Marsala L; Division of Oncology, Siteman Cancer Center, and., Marin ND; Division of Oncology, Siteman Cancer Center, and., Foster M; Division of Oncology, Siteman Cancer Center, and., Schappe T; Division of Oncology, Siteman Cancer Center, and., Fatima H; Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Becker-Hapak M; Division of Oncology, Siteman Cancer Center, and., Zhou AY; Division of Oncology, Siteman Cancer Center, and., Hwang K; Division of Oncology, Siteman Cancer Center, and., Jacobs MT; Division of Oncology, Siteman Cancer Center, and., Russler-Germain DA; Division of Oncology, Siteman Cancer Center, and., Mace EM; Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Berrien-Elliott MM; Division of Oncology, Siteman Cancer Center, and., Payton JE; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA., Fehniger TA; Division of Oncology, Siteman Cancer Center, and. |
| Abstrakt: |
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. |
