Abstract
A population of NK cells expressing the activating receptor NKG2C and the maturation marker CD57 expands in response to human CMV (HCMV) infection. CD3-CD56dimCD57+NKG2C+ NK cells are similar to CD8+ memory T cells with rapid and robust effector function upon restimulation, 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 Abs 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 cocultured 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. We believe our study has important implications for cancer immunotherapy and propose that exhausted NK cells could be targeted with inhibitory checkpoint receptor blockade.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3770-3785 |
| Number of pages | 16 |
| Journal | Journal of Clinical Investigation |
| Volume | 129 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 3 2019 |
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Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming. / Merino, Aimee; Zhang, Bin; Dougherty, Philip; Luo, Xianghua; Wang, Jinhua; Blazar, Bruce R.; Miller, Jeffrey S.; Cichocki, Frank.
In: Journal of Clinical Investigation, Vol. 129, No. 9, 03.09.2019, p. 3770-3785.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming
AU - Merino, Aimee
AU - Zhang, Bin
AU - Dougherty, Philip
AU - Luo, Xianghua
AU - Wang, Jinhua
AU - Blazar, Bruce R.
AU - Miller, Jeffrey S.
AU - Cichocki, Frank
PY - 2019/9/3
Y1 - 2019/9/3
N2 - A population of NK cells expressing the activating receptor NKG2C and the maturation marker CD57 expands in response to human CMV (HCMV) infection. CD3-CD56dimCD57+NKG2C+ NK cells are similar to CD8+ memory T cells with rapid and robust effector function upon restimulation, 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 Abs 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 cocultured 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. We believe our study has important implications for cancer immunotherapy and propose that exhausted NK cells could be targeted with inhibitory checkpoint receptor blockade.
AB - A population of NK cells expressing the activating receptor NKG2C and the maturation marker CD57 expands in response to human CMV (HCMV) infection. CD3-CD56dimCD57+NKG2C+ NK cells are similar to CD8+ memory T cells with rapid and robust effector function upon restimulation, 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 Abs 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 cocultured 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. We believe our study has important implications for cancer immunotherapy and propose that exhausted NK cells could be targeted with inhibitory checkpoint receptor blockade.
UR - http://www.scopus.com/inward/record.url?scp=85068441048&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068441048&partnerID=8YFLogxK
U2 - 10.1172/JCI125916
DO - 10.1172/JCI125916
M3 - Article
C2 - 31211698
AN - SCOPUS:85068441048
VL - 129
SP - 3770
EP - 3785
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -