A population of Natural Killer (NK) cells expressing the activating receptor NKG2C and the maturation marker CD57 expands in response to human cytomegalovirus (HCMV) infection. CD3-CD56dimCD57+NKG2C+ NK cells are similar to CD8+ memory T cells with rapid and robust effector function upon re-stimulation, persistence, and epigenetic remodeling of the IFNG locus. Chronic antigen stimulation drives CD8+ memory T cell proliferation while also inducing genome-wide epigenetic reprograming and dysfunction. We hypothesized that chronic stimulation could similarly induce epigenetic reprograming and dysfunction in NK cells. Here we show that chronic stimulation of adaptive NK cells through NKG2C using plate-bound agonistic antibodies in combination with IL-15 drove robust proliferation and activation of CD3-CD56dimCD57+NKG2C+ NK cells while simultaneously inducing high expression of the checkpoint inhibitory receptors LAG-3 and PD-1. Marked induction of checkpoint inhibitory receptors was also observed on the surface of adaptive NK cells co-cultured with HCMV-infected endothelial cells. Chronically stimulated adaptive NK cells were dysfunctional when challenged with tumor targets. These cells exhibited a pattern of epigenetic reprograming, with genome-wide alterations in DNA methylation. Our study has important implications for cancer immunotherapy and suggest that exhausted NK cells could be targeted with inhibitory checkpoint receptor blockade.
Bibliographical noteFunding Information:
We thank the University of Minnesota Genomics Center (UMGC) and the University of Minnesota Flow Cytometry Core for their services. We also thank J.P. Houchins at R&D Systems for providing all mAbs used for plate-bound stimulation experiments. This work was supported by NIH grants K99/R00 HL123638 (to FC), P30 CA77598 (to JW), P01 CA111412 (to JSM), P01 CA65493 (to JSM; BRB), R35 CA197292 (to JSM), and R01 HL56067 (to BRB), as well as by a Hematology Research Training Program grant T32 2T32HL007062 (to AM).
© 2019, American Society for Clinical Investigation.
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