Unraveling exhaustion in adaptive and conventional NK cells

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30 Scopus citations


Immune exhaustion in T cells significantly impacts their ability to control malignancies and infections, and its discovery has led to revolutionary therapies for cancer in the form of checkpoint blockade. NK cells, like T cells, are lymphocytes that recognize virally infected and malignantly transformed cells. However, it remains unclear if NK cells are similarly susceptible to exhaustion. In this review, the aims are to summarize what is currently known and to identify key areas of variability that skew the scientific literature on NK cell exhaustion. A lack of consensus on the defining features of NK cell dysfunctional states such as senescence, suppression, and exhaustion has made a comparison between studies difficult. There are also significant differences in the biology of NK cell subsets with long-lived, adaptive NK cells sharing an epigenetic signature closer to memory CD8+ T cells than to conventional NK cells. Very different checkpoint receptor expression and effector functions have been shown in adaptive versus conventional NK cells chronically exposed to activating signals. Adaptive NK cells develop in individuals with cytomegalovirus (CMV) infection and well over half of the human population worldwide is CMV seropositive by adulthood. Despite this high prevalence, most studies do not account or control for this population. This may contribute to some of the variability reported in the literature on checkpoint receptor expression on NK cells. In this review, the protective role that exhaustion plays in T cells will also be discussed and the evidence for a similar phenomenon in NK cells will be examined.

Original languageEnglish (US)
Pages (from-to)1361-1368
Number of pages8
JournalJournal of Leukocyte Biology
Issue number4
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
This work was supported by the NIH grant K99/R00 HL123638 (to F.C.), P01 CA111412 (to J.S.M.), P01 CA65493 (to J.S.M.), and T32 2T32HL007062 (A.M.). The graphics in this paper were generated with BioRender.

Publisher Copyright:
©2020 Society for Leukocyte Biology


  • Exhaustion
  • LAG-3
  • Natural Killer
  • PD-1
  • adaptive
  • checkpoint receptor


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