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Review
. 2021 Apr 5;218(4):e20201731.
doi: 10.1084/jem.20201731.

Virus-specific NK cell memory

Sam Sheppard  1 , Joseph C Sun  1   2
Affiliations
Review

Virus-specific NK cell memory

Sam Sheppard et al. J Exp Med. .

Abstract

NK cells express a limited number of germline-encoded receptors that identify infected or transformed cells, eliciting cytotoxicity, effector cytokine production, and in some circumstances clonal proliferation and memory. To maximize the functional diversity of NK cells, the array and expression level of surface receptors vary between individual NK cell "clones" in mice and humans. Cytomegalovirus infection in both species can expand a population of NK cells expressing receptors critical to the clearance of infected cells and generate a long-lived memory pool capable of targeting future infection with greater efficacy. Here, we discuss the pathways and factors that regulate the generation and maintenance of effector and memory NK cells and propose how this understanding may be harnessed therapeutically.

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Conflict of interest statement

Disclosures: The authors declare no competing interests exist.

Figures

Figure 1.
Figure 1.
Regulation of proliferation and survival is critical to memory NK cell formation during MCMV infection. (A) Proliferation. IL-12 activates STAT4, which drives a cascade of proliferation-promoting transcription factors (e.g., IRF8 and Zbtb32) in NK cells that results in the suppression of BLIMP-1, in addition to up-regulating factors such as MyD88 and the neurotransmitter receptor ADRB2. Along with IL-12 and STAT4 signaling, IL-18 signals via MyD88 in NK cells, and together, these two proinflammatory cytokines drive Ly49H+ NK cell proliferation. (B) Survival. IL-12 and IL-18 also cooperate to regulate SOCS1 and NOXA through a microRNA-155 (miR-155)–dependent mechanism. Signaling through IFNαR induces the ISGF3 complex (consisting of STAT1, STAT2, and IRF9), protecting NK cells against NKG2D-mediated “fratricide” and ensuring their survival. Signaling through the costimulatory molecule DNAM-1 also facilitates survival in a PKCη- and FYN-dependent manner. Expression of RAG is critical to induction of DNA damage repair pathways that maintain viability during rapid cell division. Dashed lines represent induction of mRNA. NKG2DL, NKG2D ligand.
Figure 2.
Figure 2.
Human and mouse memory NK cell traits. As NK cells differentiate from naive to memory cells during viral infection, they become less responsive to certain cytokines but more responsive to activating receptor engagement. This transition can be attributed in part to changes in the overall expression of receptors, adaptor molecules, and signaling proteins regulated at the epigenetic and transcriptional levels.
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