Human Cytomegalovirus Infection Enhances NK Cell Activity In Vitro

Tschan-Plessl, Astrid; Stangel, Martin; Schmied, Laurent; Retière, Christelle; Hirsch, Hans H.; Garzoni, Christian; Delden, Christian van; Boggian, Katia; Mueller, Nicolas J.; Berger, Christoph; Villard, Jean; Manuel, Oriol; Meylan, Pascal; Terszowski, Grzegorz

doi:10.1097/txd.0000000000000605

Cited by 9 publications

(8 citation statements)

References 41 publications

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“…Intriguingly, CD56 dim NK cells from CMV-positive donors had a significantly higher capacity to secrete IFN-γ than those from CMV-negative individuals (Figure 1F). These data are in line with previous reports that established a role for CMV in shaping immune reactivity of CD56 dim NK cells both in vitro and in vivo [34,35], a phenomenon that was not recapitulated in the CD56 neg NK cell subset (Figure 1F). In all, our data suggested that CD56 neg NK cells had reduced cytotoxic capacity and IFN-γ production compared to CD56 dim NK cells, a feature that was further pronounced in the context of CMV / EBV co-infection.…”

Section: Resultssupporting

confidence: 93%

CD56-negative NK cells with impaired effector function expand in CMV and EBV co-infected healthy donors with age

Müller-Durovic

Grählert

Devine

et al. 2019

Aging

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Natural killer cells lacking expression of CD56 (CD56neg NK cells) have been described in chronic HIV and hepatitis C virus infection. Features and functions of CD56neg NK cells in the context of latent infection with CMV and / or EBV with age are not known. In a cohort of healthy donors >60 years of age, we found that co-infection with CMV and EBV drives expansion of CD56neg NK cells. Functionally, CD56neg NK cells displayed reduced cytotoxic capacity and IFN-γ production, a feature that was enhanced with CMV / EBV co-infection. Further, the frequency of CD56neg NK cells correlated with accumulation of end-stage-differentiated T cells and a reduced CD4 / CD8 T cell ratio, reflecting an immune risk profile. CD56neg NK cells had a mature phenotype characterized by low CD57 and KIR expression and lacked characteristics of cell senescence. No changes in their activating NK cell receptor expression, and no upregulation of the negative co-stimulation receptors PD-1 or TIM-3 were observed. In all, our data identify expansion of dysfunctional CD56neg NK cells in CMV+EBV+ elderly individuals suggesting that these cells may function as shape-shifters of cellular immunity and argue for a previously unrecognized role of EBV in mediating immune risk in the elderly.

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Section: Resultssupporting

confidence: 93%

CD56-negative NK cells with impaired effector function expand in CMV and EBV co-infected healthy donors with age

Müller-Durovic

Grählert

Devine

et al. 2019

Aging

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“…CD56 dim NK cells expanded after viremia, while long-term after transplant the ratio of CD56 dim to CD56 bright NK cells was equivalent between CMV PCR + and PCR – patients. Delayed repopulation of these memory-like CD56 dim NK cells has previously been associated with CMV disease in stem cell and kidney transplant recipients ( 13 , 14 , 42 ). There is also evidence of long-term persistence of these cells following viremia ( 43 ).…”

Section: Discussionmentioning

confidence: 97%

“…CMV primary infection or reactivation is a significant problem in transplant recipients receiving immunosuppressive therapy, with direct effects from CMV disease and indirect immunopathological effects (12). In SOT, CMV viremia and symptomatic disease are associated with chronic graft dysfunction and rejection (12), and NK and CD8 T cell number and magnitude have been implicated in control of CMV post-transplant and graft outcome (13)(14)(15)(16). For this reason, transplant recipients receive antiviral prophylaxis with additional routine screening for CMV DNA in the periphery to monitor control of infection (17).…”

Section: Introductionmentioning

confidence: 99%

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant

Pickering¹,

Sen²,

Arakawa-Hoyt³

et al. 2021

JCI Insight

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Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant (SOT) recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity allowing CMV reactivation is critical to guiding anti-viral therapy and examining CMV's impact on outcomes of SOT. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, non-viremic recipients. Subjects were sampled three-and twelve-months post-transplant, with additional samples oneweek and one-month post-viremia. Peripheral blood mononuclear cells (PBMC) were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 T cell transcriptomes were characterized by single-cell RNA-Seq. Pre-viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56 bright NK cells. Post-viremia, mature CD56 dim NK cells and CD28 -CD8 T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28 -CD8 T cells were associated with control of viremia. These findings suggest signatures of innate activation may be prognostic for CMV reactivation posttransplant, while CD8 T cell functionality is critical for effective control of CMV.

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“…In contrast, if no such changes in NK phenotype were seen, it would add further support for the conclusion that the recipient had resisted transmission of HCMV from the donor. A single recent publication reports that significant changes in NK phenotype can be seen from 6 months posttransplant in patients with primary CMV infection …”

Section: Suggested Criteria To Evaluate Whether Active or Passive Immmentioning

confidence: 99%

Criteria to define interruption of transmission of human cytomegalovirus from organ donor to recipient

Baraniak¹,

Reeves²,

Griffiths³

2017

Reviews in Medical Virology

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SummaryIn this review article, we consider results suggesting that transmission of human cytomegalovirus (HCMV) from a donor of a solid organ to an immunologically naive individual can be reduced. Two randomized controlled trials have been conducted recently, one of active immunization of recipients pretransplant and another of passive immunization with monoclonal antibodies specific for HCMV given at the time of transplant. Although the available data are encouraging-providing evidence of a reduction in the incidence of HCMV viraemia-they fall short of what would be required to prove definitively that transmission has been completely prevented. Here, we reflect on these studies and propose a set of 5 criteria, which, if satisfied in the future, could be taken as proof that active and/or passive immunization against HCMV effectively interrupts transmission of virus from the donor. We suggest that these criteria are considered when designing future randomized controlled trials.

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Human Cytomegalovirus Infection Enhances NK Cell Activity In Vitro

Abstract: Supplemental digital content is available in the text.

Cited by 9 publications

References 41 publications

CD56-negative NK cells with impaired effector function expand in CMV and EBV co-infected healthy donors with age

CD56-negative NK cells with impaired effector function expand in CMV and EBV co-infected healthy donors with age

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant

Criteria to define interruption of transmission of human cytomegalovirus from organ donor to recipient

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