Natural killer (NK) cells are innate lymphocytes that provide critical host defense against pathogens and cancer. Originally heralded for their early and rapid effector activity, NK cells have been ...recognized over the last decade for their ability to undergo adaptive immune processes, including antigen-driven clonal expansion and generation of long-lived memory. This review presents an overview of how NK cells lithely partake in both innate and adaptive responses and how this versatility is manifest in human NK cell-mediated immunity.
Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived “memory” cells, processes poorly ...understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS)-dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to-memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes.
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•MCMV infection induces dynamic changes in NK cell mitochondrial quality•Autophagy is essential for the generation of NK cell memory•Pharmacologic induction of autophagy enhances NK cell memory formation•Mitophagy is required for anti-viral NK cell survival through removal of ROS
After viral infection, the majority of effector lymphocytes undergo rapid apoptosis. However, it is unclear how a subset of these cells persist to form immunological memory. Sun and colleagues demonstrate that mitophagy promotes the survival of virus-specific NK cells during the contraction phase to promote memory.
Natural killer (NK) cells play critical roles defending against tumors and pathogens. We show that mice lacking both transcription factors Eomesodermin (Eomes) and T-bet failed to develop NK cells. ...Developmental stability of immature NK cells constitutively expressing the death ligand TRAIL depended on T-bet. Conversely, maturation characterized by loss of constitutive TRAIL expression and induction of Ly49 receptor diversity and integrin CD49b (DX5
+) required Eomes. Mature NK cells from which Eomes was deleted reverted to phenotypic immaturity if T-bet was present or downregulated NK lineage antigens if T-bet was absent, despite retaining expression of Ly49 receptors. Fetal and adult hepatic hematopoiesis restricted Eomes expression and limited NK development to the T-bet-dependent, immature stage, whereas medullary hematopoiesis permitted Eomes-dependent NK maturation in adult mice. These findings reveal two sequential, genetically separable checkpoints of NK cell maturation, the progression of which is metered largely by the anatomic localization of hematopoiesis.
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► NK cells are absent in mice lacking both T-bet and Eomes ► T-bet is essential to stabilize immature, TRAIL
+ NK cells ► Eomes is required to develop and partially maintain mature, DX5
+ NK cells ► NK cells lose NK antigens after deletion of T-bet and Eomes
Natural Killer Cell Memory O’Sullivan, Timothy E.; Sun, Joseph C.; Lanier, Lewis L.
Immunity (Cambridge, Mass.),
10/2015, Letnik:
43, Številka:
4
Journal Article
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Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner and then undergo cell ...death. Recently, however, NK cells have been shown to possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. In this review, we discuss evidence of NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes.
Recent advances in the field of natural killer (NK) cell biology have revealed that these innate lymphocytes exhibit functional properties of immunological memory. O’Sullivan, Sun, and Lanier review these advances and provide insight into the mechanisms governing the generation of NK cell memory.
MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of ...hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3′ UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context.
•miR-155-mediated SOCS1 repression contributes to Treg cell competitive fitness•Th17 cell generation is independent of SOCS1 regulation by miR-155•CD8+ T cells during chronic but not acute infection need SOCS1 repression by miR-155•NK cell response to MCMV infection requires miR-155-mediated SOCS1 repression
A single microRNA (miRNA) can regulate expression of hundreds of target genes, but the biological consequences of individual miRNA-mRNA interactions remain unclear. Rudensky and colleagues show that miR-155-dependent regulation of SOCS1 in different immune cell subsets has cell type- and biological context-dependent in vivo relevance.
Natural killer (NK) cells survey host tissues for signs of infection, transformation or stress and, true to their name, kill target cells that have become useless or are detrimental to the host. For ...decades, NK cells have been classified as a component of the innate immune system. However, accumulating evidence in mice and humans suggests that, like the B and T cells of the adaptive immune system, NK cells are educated during development, possess antigen-specific receptors, undergo clonal expansion during infection and generate long-lived memory cells. In this Review, we highlight the many stages that an NK cell progresses through during its remarkable lifetime, discussing similarities and differences with its close relative, the cytotoxic CD8(+) T cell.
One of the hallmarks of the vertebrate adaptive immune system is the prolific expansion of individual cell clones that encounter their cognate antigen. More recently, however, there is growing ...evidence for the clonal expansion of innate lymphocytes, particularly in the context of pathogen challenge. Clonal expansion not only serves to amplify the number of specific lymphocytes to mount a robust protective response to the pathogen at hand but also results in selection and differentiation of the responding lymphocytes to generate a multitude of cell fates. Here, we summarize the evidence for clonal expansion in innate lymphocytes, which has primarily been observed in natural killer (NK) cells responding to cytomegalovirus infection, and consider the requirements for such a response in NK cells in light of those for T cells. Furthermore, we discuss multiple aspects of heterogeneity that both contribute to and result from the fundamental immunological process of clonal expansion, highlighting the parallels between innate and adaptive lymphocytes, with a particular focus on NK cells and CD8
T cells.
Although NK cells are considered part of the innate immune system, recent studies have demonstrated the ability of Ag-experienced NK cells to become long-lived and contribute to potent recall ...responses similar to T and B cells. The precise signals that promote the generation of a long-lived NK cell response are largely undefined. In this article, we demonstrate that NK cells require IL-18 signaling to generate a robust primary response during mouse CMV (MCMV) infection but do not require this signal for memory cell maintenance or recall responses. IL-12 signaling and STAT4 in activated NK cells increased the expression of the adaptor protein MyD88, which mediates signaling downstream of the IL-18 and IL-1 receptors. During MCMV infection, NK cells required MyD88, but not IL-1R, for optimal expansion. Thus, an IL-18-MyD88 signaling axis facilitates the prolific expansion of NK cells in response to primary viral infection, but not recall responses.
•In recent years, the ability to form immunological memory has been described in many taxa, including plants, invertebrates, and vertebrates.•Innate immune and non-immune cells, including NK cells, ...ILCs, macrophages, and epithelial cells have now been reported to possess features of immunological memory.•Epigenetic modifications play important roles in memory formation in immune and non-immune cells.
Immunological memory is defined by the ability of the host to recognise and mount a robust secondary response against a previously encountered pathogen. Classic immune memory is an evolutionary adaptation of the vertebrate immune system that has been attributed to adaptive lymphocytes, including T and B cells. In contrast, the innate immune system was known for its conserved, non-specific roles in rapid host defence, but historically was considered to be unable to generate memory. Recent studies have challenged our understanding of innate immunity and now provides a growing body of evidence for innate immune memory. However, in many species and in various cell types the underlying mechanisms of immune 'memory' formation remain poorly understood. The purpose of this review is to explore and summarise the emerging evidence for immunological ‘memory’ in plants, invertebrates, and vertebrates.
The emergence of recombination-activating genes (RAGs) in jawed vertebrates endowed adaptive immune cells with the ability to assemble a diverse set of antigen receptor genes. In contrast, innate ...lymphocytes, such as natural killer (NK) cells, are not believed to require RAGs. Here, we report that NK cells unable to express RAGs or RAG endonuclease activity during ontogeny exhibit a cell-intrinsic hyperresponsiveness but a diminished capacity to survive following virus-driven proliferation, a reduced expression of DNA damage response mediators, and defects in the repair of DNA breaks. Evidence for this novel function of RAG has also been observed in T cells and innate lymphoid cells (ILCs), revealing an unexpected role for RAG proteins beyond V(D)J recombination. We propose that DNA cleavage events mediated by RAG endow developing adaptive and innate lymphocytes with a cellular “fitness” that safeguards their persistence later in life during episodes of rapid proliferation or cellular stress.
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•RAG expression in NK cell ontogeny defines a cell-intrinsic differentiation program•RAG plays a novel role in the functional specialization of NK cell subsets•RAG-deficient lymphocytes exhibit a reduced DNA damage response and cellular fitness•A physiological role for RAG proteins exists outside of V(D)J recombination
A novel role for the RAG proteins, unrelated to antigen receptor generation but, rather, regulating the cellular fitness of NK cells, adds to a growing body of evidence implicating “controlled” DNA damage in the regulation of gene expression, cell development, and cell fate in eukaryotes.
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