Foley, B, Cooley, S, Verneris, MR, Pitt, M, Curtsinger, J, Luo, X et al.. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119: 2665-2674

Department of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
Blood (Impact Factor: 10.45). 12/2011; 119(11):2665-74. DOI: 10.1182/blood-2011-10-386995
Source: PubMed


During mouse cytomegalovirus (CMV) infection, a population of Ly49H(+) natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C(+) NK cells expanded and were potent producers of IFNγ. NKG2C(+) NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulin-like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56(dim) NK cells. Strikingly, increased frequencies of NKG2C(+) NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C(+) NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.

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    • "In humans, elevated and variable frequencies of memory-like NK cells, characterized by the expression of the activation receptor NKG2C, have been observed in association with prior infection by human cytomegalovirus (HCMV) (Gumá et al., 2004, 2006b; Monsivá is-Urenda et al., 2010; Muntasell et al., 2013; Noyola et al., 2012), a common herpesvirus that establishes life-long latent infection in the majority of human populations (Dowd et al., 2009). It has also been observed that NKG2C + NK cells expand in number in transplant patients experiencing HCMV reactivation and persist long term, even after clearance of active infection (Della Chiesa et al., 2012; Foley et al., 2012; Lopez-Vergè s et al., 2011). NKG2C might be a useful marker for identifying memory-like NK cells, but more recent studies have shown that HCMV-infected individuals also have expanded populations of NK cells that persist long term and express certain activation forms of killer-cell immunoglobulin-like receptors (KIRs), including KIR2DS2 and KIR2DS4, even in the absence of NKG2C (Bé ziat et al., 2013; Della Chiesa 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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    • "Subsequent observations in human beings showed that also human CMV infection leads to expansion of a subset of NKG2C+ NK cells (32, 33) with memory-like properties. Increased proportions of NKG2C+ NK cells persist (34) after acute infection into latency, and may be observed also after bone marrow transplantation (34, 35). Additional evidences of transient NK cell expansions in human beings are provided by infection with chikungunya and hantavirus (36, 37), and may persist up to 60–90 days. "
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    ABSTRACT: Natural killer (NK) cell function is regulated by a balance between the triggering of activating and inhibitory receptors expressed on their surface. A relevant effort has been focused so far on the study of KIR carriage/expression setting the basis for NK cell education and self-tolerance. Focus on the evolution and regulation of activating NK receptors has lagged behind so far. Our understanding of activating receptor expression and regulation has recently improved by evidences derived from in vitro and in vivo studies. Virus infection - either acute or chronic - determines preferential expansion of NK cells with specific phenotype, activating receptors, and with recall-like functional activity. Studies on patients with viral infection (HIV and HCV) and specific diverging clinical courses confirm that inter-individual differences may exist in baseline expression of natural cytotoxicity receptors (NKp46 and NKp30). The findings that patients with divergent clinical courses have different kinetics of activating receptor density expression upon NK cell activation in vitro provide an additional, time-dependent, functional parameter. Kinetic changes in receptor expression thus represent an additional parameter to basal receptor density expression. Different expression and inducibilities of activating receptors on NK cells contribute to the high diversity of NK cell populations and may help our understanding of the inter-individual differences in innate responses that underlie divergent disease courses.
    Frontiers in Immunology 07/2014; 5:305. DOI:10.3389/fimmu.2014.00305
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    • "Recently, prior exposure to CMV and Hantavirus infection has been linked to altered populations of human NK cells, resulting in an expanded NKG2C+ NK cells that exhibit enhanced functionality upon restimulation [44–46]. While not a focus of this review, such prior experience of CMV results in a functionally enhanced NKG2C+ NK cell population in solid organ or bone marrow transplantation patients [44, 45]. Once appropriately triggered, the NK cell responds by killing the target [47] and producing cytokines including IFN-γ, TNF-α, GM-CSF, MIP-1α, and others [3]. "
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    ABSTRACT: Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.
    06/2014; DOI:10.1155/2014/205796
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