Emerging data provide evidence that natural killer (NK) cells can contribute to immunological memory, an activity that has traditionally been associated with T cells and B cells. Three main types of NK cell memory exist, namely hapten-specific NK cell memory, virus-specific NK cell memory and cytokine-induced NK cell memory.
Distinct receptor–ligand interactions and distinct cytokine milieus lead to the generation of antigen-specific memory NK cells. Cytokine-induced memory NK cells can be generated by exposure to inflammatory cytokines even in the absence of a defined antigen.
The different types of memory NK cells differ in terms of their tissue localization patterns. For example, hapten-specific memory NK cells reside in the liver, influenza virus-specific memory NK cells reside in the liver and lung, and mouse cytomegalovirus (MCMV)-specific NK cells and cytokine-induced memory NK cells are systemically distributed.
Most of our mechanistic knowledge of the signals that drive the generation of virus-specific memory NK cells originates from experiments using MCMV infection as a model system. These studies have identified LY49H as the MCMV-specific activating NK cell receptor and m157 as the cognate viral ligand recognized by LY49H.
The basic concepts derived from studying NK cell memory might lead to novel strategies for refining vaccination protocols to improve treatments for infectious diseases.
It is possible that NK cell memory activity could be exploited for cancer therapy. Lessons learned from the study of NK cell memory could help with the design of better expansion protocols for adoptive NK cell therapy, for the manufacturing of chimeric antigen receptor (CAR)-engineered NK cells and for improving NK cell-based therapies that rely on antibody-dependent cellular cytotoxicity (ADCC).
Immunological memory can be defined as a quantitatively and qualitatively enhanced immune response upon rechallenge. For natural killer (NK) cells, two main types of memory exist. First, similarly to T cells and B cells, NK cells can exert immunological memory after encounters with stimuli such as haptens or viruses, resulting in the generation of antigen-specific memory NK cells. Second, NK cells can remember inflammatory cytokine milieus that imprint long-lasting non-antigen-specific NK cell effector function. The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.
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The authors cordially thank A. Stojanovic and M. Correia from the Cerwenka laboratory for critically reading the manuscript and for many helpful discussions. They also thank A. Rölle, N. Jing and J. Pollmann for helping with the preparation of the figures. L.L.L. is an American Cancer Society Professor and is funded by US National Institutes of Health grants (AI066897 and AI068129). A.C. is funded by grants from the German Cancer Aid, Deutsche Krebshilfe (110442 and 111455) and from the German Research Foundation (DFG; RTG2099).
The authors declare no competing financial interests.
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Cerwenka, A., Lanier, L. Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 16, 112–123 (2016). https://doi.org/10.1038/nri.2015.9
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