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Updated: Dec 13, 2025
Expansion, Purification, and Functional Assessment of Human Peripheral Blood NK Cells
Published on: February 2, 2011
Unraveling exhaustion in adaptive and conventional NK cells
Aimee M Merino1, Hansol Kim1, Jeffrey S Miller1
1Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Abstract:
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.
Insights
Natural killer (NK) cells may experience exhaustion, similar to T cells, impacting their function. Variability in research highlights the need for clearer definitions and consideration of adaptive NK cells, especially in cytomegalovirus-positive individuals.
Area of Science:
- Immunology
- Cellular Biology
- Cancer Research
Background:
- Immune exhaustion in T cells is a critical factor in controlling infections and malignancies, leading to successful cancer immunotherapies.
- Natural killer (NK) cells, like T cells, are lymphocytes involved in recognizing and eliminating virally infected and malignant cells.
- The susceptibility of NK cells to exhaustion, analogous to T cells, remains an area of active investigation and debate.
Purpose of the Study:
- To review current knowledge on NK cell exhaustion and identify sources of variability in the scientific literature.
- To examine the defining features of NK cell dysfunctional states, including senescence, suppression, and exhaustion.
- To explore the potential protective role of exhaustion in NK cells, mirroring its function in T cells.
Main Methods:
- Literature review synthesizing existing research on NK cell exhaustion and related dysfunctional states.
- Comparative analysis of T cell exhaustion and potential NK cell exhaustion mechanisms.
- Examination of differences between adaptive and conventional NK cell subsets, including epigenetic and functional characteristics.
Main Results:
- A lack of consensus exists regarding the defining characteristics of NK cell exhaustion, hindering cross-study comparisons.
- Significant biological differences between adaptive and conventional NK cell subsets influence their response to chronic activation.
- Adaptive NK cells, prevalent in cytomegalovirus-seropositive individuals, exhibit distinct checkpoint receptor expression and effector functions.
- Variability in studies may stem from not accounting for the adaptive NK cell population, common due to high cytomegalovirus prevalence.
Conclusions:
- Clarifying the definitions of NK cell exhaustion and related states is crucial for advancing research.
- The unique biology of adaptive NK cells necessitates specific consideration in studies of NK cell dysfunction.
- Further investigation is required to fully understand the mechanisms and implications of NK cell exhaustion.
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