Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion

Jacob A. Myers, Dawn Schirm, Laura Bendzick, Rachel Hopps, Carly Selleck, Peter Hinderlie, Martin Felices, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


NK cell exhaustion is caused by chronic exposure to activating stimuli during viral infection, tumorigenesis, and prolonged cytokine treatment. Evidence suggests that exhaustion may play a role in disease progression. However, relative to T cell exhaustion, the mechanisms underlying NK cell exhaustion and methods of reversing it are poorly understood. Here, we describe a potentially novel in vitro model of exhaustion that uses plate-bound agonists of the NK cell activating receptors NKp46 and NKG2D to induce canonical exhaustion phenotypes. In this model, prolonged activation resulted in downregulation of activating receptors, upregulation of checkpoint markers, decreased cytokine production and cytotoxicity in vitro, weakened glycolytic capacity, and decreased persistence, function, and tumor control in vivo. Furthermore, we discovered a beneficial effect of NK cell inhibitory receptor signaling during exhaustion. By simultaneously engaging the inhibitory receptor NKG2A during activation in our model, cytokine production and cytotoxicity defects were mitigated, suggesting that balancing positive and negative signals integrated by effector NK cells can be beneficial for antitumor immunity. Together, these data uncover some of the mechanisms underlying NK cell exhaustion in humans and establish our in vitro model as a valuable tool for studying the processes regulating exhaustion.

Original languageEnglish (US)
Article numbere150079
JournalJCI Insight
Issue number15
StatePublished - Aug 8 2022

Bibliographical note

Funding Information:
We would like to acknowledge the flow cytometry core and the University Imaging Centers at the University of Minnesota for exceptional service and technical support. This work was supported by the following NIH grants: P01 CA111412 and R35 CA197292 (to MF and JSM).

Publisher Copyright:
© 2022 American Society for Clinical Investigation. All rights reserved.


  • Carrier Proteins
  • Cytokines
  • Humans
  • Killer Cells, Natural
  • Neoplasms

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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