<i>NKG2C</i> zygosity influences CD94/NKG2C receptor function and the NK‐cell compartment redistribution in response to human cytomegalovirus

Muntasell, Aura; López-Montañés, María; Vera, Antonio; Heredia, Gemma; Romo, Neus; Peñafiel, Judith; Moraru, Manuela; Vila, Joan; Vilches, Carlos; López‐Botet, Miguel

doi:10.1002/eji.201343773

Cited by 83 publications

(118 citation statements)

References 40 publications

(91 reference statements)

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“…1A) (30). Expression of CD16 (FcgRIIIA) was similar in all CD56 dim NK cells, whereas the expression of the FcεRg-chain was decreased in a variable proportion of NKG2C bright but hardly in any NKG2A + NK cells (Fig.…”

Section: Phenotypic Features Of Nkg2c Bright Nk Cells In Relation To mentioning

confidence: 85%

“…HCMV + donors lacking NKG2C bright expansion had an average of 13% undifferentiated NKG2C dim NK cells (range 6-16%; Fig. 7A, 7B) (30). Samples from HCMV + individuals with NKG2C bright NK cell expansions secreted larger amounts of TNF-a and IFN-g in response to rituximab-coated 721.221 cells than those from HCMV + subjects lacking this cell population (Fig.…”

Section: Nkg2c Bright Nk Cells Influence the Overall Ab-dependent Tnfmentioning

confidence: 86%

“…The CD16A (FcgRIIIA) receptor, present on most CD56 dim NK cells is, together with NKG2D, preserved upon NKG2C bright NK cell differentiation (30). CD16 interacts with the Fc portion of a cell-bound IgG molecule, promoting target cell killing and cytokine production by resting NK cells, in contrast with the simultaneous coengagement of at least two receptors required by other activating NKRs (31,32).…”

Section: H Uman CMV (Hcmv) Is a B-herpesvirus That Infects 40-mentioning

confidence: 99%

“…Thus, two separate mechanisms may account for NKG2C bright NK cell functional specialization: 1) differentiation-driven epigenetic modifications on cytokine loci as regulators of their effector program; and 2) downregulation of NCR surface expression and CD3z-preferential coupling to CD16, associated to FcεR g-chain loss. Certain heterogeneity in the differentiation of the NKG2C bright NK cell subset is illustrated by the variable expression of CD57 or LILRB1 (16,30). Further studies are required to delineate the sequence of events leading to cytokine-producing NKG2C bright NK cells and the relation with FcεR g-chain loss.…”

Section: Differentiation Of Nkg2c Bright Nk Cells As Cytokine Producementioning

confidence: 99%

“…Finally, it is conceivable that factors modulating the HCMVinduced redistribution of the NK cell compartment, such as the NKG2C gene dose (30), could condition the overall proinflammatory cytokine secretion in HCMV-seropositive adults in different contexts.…”

Section: Differentiation Of Nkg2c Bright Nk Cells As Cytokine Producementioning

confidence: 99%

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Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Costa‐García

Vera

Moraru³

et al. 2015

The Journal of Immunology

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Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2Cbright NK cells. We analyzed NKG2Cbright NK cell responses triggered by Abs from HCMV+ sera against HCMV-infected MRC5 fibroblasts. Specific Abs promoted the degranulation (i.e., CD107a expression) and the production of cytokines (TNF-α and IFN-γ) by a significant fraction of NK cells, exceeding the low natural cytotoxicity against HCMV-infected targets. NK cell–mediated Ab-dependent cell-mediated cytotoxicity was limited by viral Ag availability and HLA class I expression on infected cells early postinfection and increased at late stages, overcoming viral immunoevasion strategies. Moreover, the presence of specific IgG triggered the activation of NK cells against Ab-opsonized cell-free HCMV virions. As compared with NKG2A+ NK cells, a significant proportion of NKG2Cbright NK cells was FcεR γ-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-α. Remarkably, the expansion of NKG2Cbright NK cells in HCMV+ subjects was related to the overall magnitude of TNF-α and IFN-γ cytokine secretion upon Ab-dependent and -independent activation. We show the power and sensitivity of the anti-HCMV response resulting from the cooperation between specific Abs and the NKG2Cbright NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2Cbright NK cells, a variable that could influence the individual responses to other pathogens and tumors.

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Section: Phenotypic Features Of Nkg2c Bright Nk Cells In Relation To mentioning

confidence: 85%

Section: Nkg2c Bright Nk Cells Influence the Overall Ab-dependent Tnfmentioning

confidence: 86%

Section: H Uman CMV (Hcmv) Is a B-herpesvirus That Infects 40-mentioning

confidence: 99%

Section: Differentiation Of Nkg2c Bright Nk Cells As Cytokine Producementioning

confidence: 99%

Section: Differentiation Of Nkg2c Bright Nk Cells As Cytokine Producementioning

confidence: 99%

See 3 more Smart Citations

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Costa‐García

Vera

Moraru³

et al. 2015

The Journal of Immunology

Self Cite

103

108

View full text Add to dashboard Cite

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Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells

et al. 2015

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CD8+ T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8 IntroductionUpon viral infection the immune system engages lymphocytes such as NK cells, CD4 + and CD8 + T cells to eliminate the virus. CD4+ and CD8 + T cells recognize viral peptides presented by MHC class II (MHC-II) and MHC class I (MHC-I) molecules respectively. CD8 + T cells specific for the infecting pathogen first undergo massive expansion before they differentiate into cytotoxic cells capable of producing high levels of effector molecules such as IL-2, IFN-γ, TNF-α, perforin and granzyme B [1, 2]. Naïve CD4 + T cells alsoCorrespondence: Dr. Klaas P. J. M. van Gisbergen e-mail: k.vangisbergen@sanquin.nl expand and develop an effector (Th1) phenotype capable of secreting copious amounts of IFN-γ, IL-2 and TNF-α to assist CD8 + T-cell and B-cell responses [3]. To avoid T-cell detection and lysis of the infected cells, viruses of the Herpesviridae family including human cytomegalovirus (HCMV) have evolved mechanisms to downregulate MHC-I molecules on infected cells [4,5]. In turn, NK cells can detect downregulation of MHC expression and produce inflammatory cytokines such as IFN-γ, TNF-α, and cytotoxic granules containing effector molecules, such as perforin and the serine protease granzyme B, to eliminate infected cells [6,7]. HCMV is a member of the Herpesviridae family of doublestranded DNA viruses and has coevolved with humans for millions of years [8]. HCMV has a broad tropism for a wide range of tissues including endothelium, fibroblasts, smooth muscle, and C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2434 Felipe A. Vieira Braga et al. Eur. J. Immunol. 2015. 45: 2433-2445 hematopoietic cells. HCMV is a prevalent human pathogen, with 40-70% of the western population being seropositive for HCMV [9]. HCMV induces persistent infection, which can be divided into acute and latent phases, and which are respectively characterized by active replication and quiescence of the virus [10]. The majority of HCMV-infected individuals do not develop any symptoms, but immunocompromised individuals, such as transplant recipients and HIV + patients, are a risk group for HCMV infection and can present with symptoms such as vascular complications [8].In order to follow T-cell responses in humans, we and others have made extensive use of instances of primary HCMV infection of transplant patients, which occurs when an HCMV − recipient receives an organ transplant from an HCMV + donor. Using this system, the data show that the initial early T-cell response against HCMV peaks on average 7 days after the first detection of circulating CMV-DNA. The T-cell response is initially dominated by CD4 + T cells that have a T-helper 1 type cytokine signature, with high production of the cytokines IFN-γ and TNF-α, but not of the classical T-helper 2 cytokine . A few days after the initial CD4 + T-cell response, HCMV-specific CD8 + T cells with high cytotoxic potential can be detected in blood. Remarkably, after th...

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Asymptomatic CMV infections in long‐term renal transplant recipients are associated with the loss of FcRγ from LIR‐1⁺ NK cells

et al. 2016

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While it is established that cytomegalovirus (CMV) disease affects NK-cell profiles, the functional consequences of asymptomatic CMV replication are unclear. Here, we characterize NK cells in clinically stable renal transplant recipients (RTRs; n = 48) >2 years after transplantation. RTRs and age-matched controls (n = 32) were stratified by their CMV serostatus and the presence of measurable CMV DNA. CMV antibody or CMV DNA influenced expression of NKG2C, LIR-1, NKp30, NKp46, and FcRγ, a signaling adaptor molecule, on CD56 dim NK cells. Phenotypic changes ascribed to CMV were clearer in RTRs than in control subjects and affected NK-cell function as assessed by TNF-α and CD107a expression. The most active NK cells were FcRγ -LIR-1 + NKG2Cand displayed high antibody-dependent cell cytotoxicity responses in the presence of immobilized CMV glycoprotein B reactive antibody. However, perforin levels in supernatants from RTRs with active CMV replication were low. Overall we demonstrate that CMV can be reactivated in symptom-free renal transplant recipients, affecting the phenotypic, and functional profiles of NK cells. Continuous exposure to CMV may maintain and expand NK cells that lack FcRγ but express LIR-1.

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NKG2C zygosity influences CD94/NKG2C receptor function and the NK‐cell compartment redistribution in response to human cytomegalovirus

Abstract: Human cytomegalovirus (HCMV) infection promotes a persistent expansion of a function-Keywords: CD94/NKG2C r Cytomegalovirus r Human r NK cells r NKG2C genotype Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 83 publications

References 40 publications

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells

Asymptomatic CMV infections in long‐term renal transplant recipients are associated with the loss of FcRγ from LIR‐1⁺ NK cells

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NKG2C zygosity influences CD94/NKG2C receptor function and the NK‐cell compartment redistribution in response to human cytomegalovirus

Abstract: Human cytomegalovirus (HCMV) infection promotes a persistent expansion of a function-Keywords: CD94/NKG2C r Cytomegalovirus r Human r NK cells r NKG2C genotype Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 83 publications

References 40 publications

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Molecular characterization of HCMV‐specific immune responses: Parallels between CD8+ T cells, CD4+ T cells, and NK cells

Asymptomatic CMV infections in long‐term renal transplant recipients are associated with the loss of FcRγ from LIR‐1+ NK cells

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Product

Resources

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Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells

Asymptomatic CMV infections in long‐term renal transplant recipients are associated with the loss of FcRγ from LIR‐1⁺ NK cells