Induced CD8[alpha] identifies human NK cells with enhanced proliferative fitness and modulates NK cell activation

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 hypothesiz...

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Published inThe Journal of clinical investigation Vol. 134; no. 15
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
LanguageEnglish
Published American Society for Clinical Investigation 01.08.2024
Subjects
Cancer
CD8 lymphocytes
Comparative analysis
Control
Development and progression
Growth
Health aspects
Identification and classification
Influence
Killer cells
Leukemia
Oncology, Experimental
Physiological aspects
United States
Missouri
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Summary: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.
ISSN:0021-9738
DOI:10.1172/JCI173602