Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function

Department of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
Blood (Impact Factor: 10.43). 12/2011; 119(11):2665-74. DOI: 10.1182/blood-2011-10-386995
Source: PubMed

ABSTRACT 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
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    • "Several groups have demonstrated that analogous antigen­specific effector and memory NK cell populations can also arise in humans during viral infection (Björkström et al., 2011; Lopez­Vergès et al., 2011; Della Chiesa et al., 2012; Foley et al., 2012). The NK cell response against mouse cy­ tomegalovirus (MCMV) infection has been historically well characterized. "
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    ABSTRACT: Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3(-/-) mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3(-/-) NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15-dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.
    Journal of Experimental Medicine 11/2013; 210(13). DOI:10.1084/jem.20130417
  • Blood 03/2012; 119(11):2438-9. DOI:10.1182/blood-2012-01-400739
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