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Induced CD8α identifies human NK cells with enhanced proliferative fitness and modulates NK cell activation
Celia C. Cubitt, … , Jacqueline E. Payton, Todd A. Fehniger
Celia C. Cubitt, … , Jacqueline E. Payton, Todd A. Fehniger
Published May 28, 2024
Citation Information: J Clin Invest. 2024;134(15):e173602. https://doi.org/10.1172/JCI173602.
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Research Article Immunology Article has an altmetric score of 16

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

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Abstract

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.

Authors

Celia C. Cubitt, Pamela Wong, Hannah K. Dorando, Jennifer A. Foltz, Jennifer Tran, Lynne Marsala, Nancy D. Marin, Mark Foster, Timothy Schappe, Hijab Fatima, Michelle Becker-Hapak, Alice Y. Zhou, Kimberly Hwang, Miriam T. Jacobs, David A. Russler-Germain, Emily M. Mace, Melissa M. Berrien-Elliott, Jacqueline E. Payton, Todd A. Fehniger

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Figure 3

CD8α does not mark a distinct, terminally differentiated population.

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CD8α does not mark a distinct, terminally differentiated population.
(A ...
(A and B) Bulk RNA-Seq was performed on freshly isolated (A) CD56bright or (B) CD56dim NK cells sorted on the basis of CD8α expression (CD3–CD19–CD14–). Data are shown as the log2-normalized expression of protein-coding genes in CD8α+/– cell populations. Red dots indicate genes that were statistically significantly differentially expressed (adjusted P < 0.05). n = 6 unique donors. The R2 value was derived from simple linear regression of gene expression data. (C and D). Peripheral blood NK cells were stained for the expression of markers of NK maturation. (C) CD56dim NK cell maturation stages were identified based on expression of NKG2A, KIR (KIR3DL1, KIR2DL1, and KIR2DL2/3), and CD57, with maturation increasing from left to right. Data are shown as the percentage of each subset that was positive for CD8α expression. n = 28 donors. (D) Expression of CD8α within NKG2A–CD56brightKIR– or KIR+ (KIR3DL1+, KIR2DL1+, and KIR2DL2/3+) NK cells. n = 11 donors. Data represent the mean ± SEM. **P < 0.01 and ****P < 0.0001, by (C) 2-way ANOVA with Holm-Šídák correction for multiple comparisons and (D) paired, 2-tailed Student’s t test.

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