Adaptive Immune Features of Natural Killer Cells

Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, California 94143, USA.
Nature (Impact Factor: 41.46). 02/2009; 457(7229):557-61. DOI: 10.1038/nature07665
Source: PubMed


In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.

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    • "In mice, CMV infection results in the expansion of Ly49H þ NK cells which recognize the viral protein m157. Akin to memory CD8 þ T cells, these cells proliferate faster and display stronger effector function upon re-exposure to CMV (Sun et al., 2009). While such adaptive NK cell responses have been mostly documented in mice, there appears to be a similar plasticity in Rhesus Macaques (Reeves et al., 2015) and in the human NK cell compartment (Bjorkstrom et al., 2011), supporting the notion that NK cells exhibit adaptive behavior. "
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    ABSTRACT: Natural killer (NK) cells are innate lymphocytes with a refined ability to recognize transformed cells through a broad array of activating receptors in combination with stochastically expressed inhibitory receptors that recognize MHC-class I. Recent advances in NK cell biology have revealed a high degree of functional plasticity that can be attributed to dynamic cell-to-cell interactions in concert with transcriptional and epigenetic reprogramming. Here, we discuss how new insights into the adaptive behavior of NK cells pave the way for next generation cell therapy based on guided differentiation and selective expansion of particularly cytotoxic NK cell subsets.
    Molecular oncology 10/2015; DOI:10.1016/j.molonc.2015.10.001 · 5.33 Impact Factor
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    • "NK cells constitute a critical component of innate immunity and serve as a first line of defense against malignancy and viral infections , particularly herpesvirus infections (Biron et al., 1989; Orange, 2002; Vivier et al., 2011). Many recent studies have revealed adaptive immune or ''memory-like'' properties of NK cells, including long-term persistence and enhanced functional responsiveness, after pathogen infection or exposure to other stimuli (Bé ziat et al., 2012; Cooper et al., 2009; Foley et al., 2012; Gumá et al., 2004; Lopez-Vergè s et al., 2011; O'Leary et al., 2006; Paust et al., 2010; Petitdemange et al., 2011; Sun et al., 2009). Although some of these characteristics might be transient or reflect a pre-activation state, it is also possible that some NK cells have undergone stable changes that serve to maintain memory-like properties, analogous to changes that occur during the differentiation of memory T cells (Farber et al., 2014). "
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    ABSTRACT: Long-lived "memory-like" NK cells have been identified in individuals infected by human cytomegalovirus (HCMV), but little is known about how the memory-like NK cell pool is formed. Here, we have shown that HCMV-infected individuals have several distinct subsets of memory-like NK cells that are often deficient for multiple transcription factors and signaling proteins, including tyrosine kinase SYK, for which the reduced expression was stable over time and correlated with epigenetic modification of the gene promoter. Deficient expression of these proteins was largely confined to the recently discovered FcRγ-deficient NK cells that display enhanced antibody-dependent functional activity. Importantly, FcRγ-deficient NK cells exhibited robust preferential expansion in response to virus-infected cells (both HCMV and influenza) in an antibody-dependent manner. These findings suggest that the memory-like NK cell pool is shaped and maintained by a mechanism that involves both epigenetic modification of gene expression and antibody-dependent expansion. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 03/2015; 42(3):431-42. DOI:10.1016/j.immuni.2015.02.013 · 21.56 Impact Factor
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    • "+ NK cells that persist for more than 25 days after infection with MCMV [Bezman et al., 2012; Nabekura et al., 2014; Sun et al., 2009a]; "
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    ABSTRACT: Recent studies have demonstrated that natural killer (NK) cells are able to undergo clonal expansion and contraction and to generate self-renewing memory cells after infection with mouse cytomegalovirus (MCMV). It is unclear whether all or only certain subsets preferentially contribute to the generation of memory NK cells. Here, we show that memory NK cells predominantly arise from killer cell lectin-like receptor G1 (KLRG1)-negative NK cell progenitors, whereas KLRG1-positive NK cells have limited capacity for expansion during infection with MCMV. Unexpectedly, the frequency of KLRG1-positive NK cells is significantly affected by the presence of T cells in the host and potentially by the host microbiota. Our findings demonstrate that excessive availability of interleukin (IL)-15 may erode the pool of memory progenitors, resulting in the decreased efficiency of memory generation in the NK cell lineage. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 01/2015; 10(2). DOI:10.1016/j.celrep.2014.12.025 · 8.36 Impact Factor
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