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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    • "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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    • "These homeostatic or spacedriven long-lived memory NK cells reside for months in both lymphoid and non-lymphoid sites and can rapidly mount protective secondary responses when virus is reencountered. Thus, these homeostatically expanded NK cells undergo all four phases, namely the expansion, contraction, memory maintenance and recall response as memory T-cells [9]. In this review we present an overview on biology of NK cells, the interactions of NK cells with other immune cells, strategies to modulate NK cell activity and the use of NK cells in cancer immunotherapy. "
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    ABSTRACT: Abstract Natural Killer (NK) cells are innate immune effectors that are primarily involved in immunosurveillance to spontaneously eliminate malignantly transformed and virally infected cells without prior sensitization. NK cells trigger targeted attack through release of cytotoxic granules, and secrete various cytokines and chemokines to promote subsequent adaptive immune responses. NK cells selectively attack target cells with diminished major histocompatibility complex (MHC) class I expression. This “Missing-self” recognition by NK cells at first puzzled researchers in the early 1990s, and the mystery was solved with the discovery of germ line encoded killer immunoglobulin receptors that recognize MHC-I molecules. This review summarizes the biology of NK cells detailing the phenotypes, receptors and functions; interactions of NK cells with dendritic cells (DCs), macrophages and T cells. Further we discuss the various strategies to modulate NK cell activity and the practice of NK cells in cancer immunotherapy employing NK cell lines, autologous, allogeneic and genetically engineered cell populations. Keywords NK cells; Cancer; Immunotherapy; Adoptive cell transfer
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.020 · 5.62 Impact Factor
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