Research Paper Volume 11, Issue 2 pp 724—740

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

Bojana Müller-Durovic1, , Jasmin Grählert1, , Oliver P. Devine2, , Arne N. Akbar2, , Christoph Hess1,3, ,

  • 1 University Hospital Basel, Department of Biomedicine, Basel, Switzerland
  • 2 Division of Infection and Immunity, University College London, London, UK
  • 3 Department of Medicine, University of Cambridge, Cambridge, UK
* Equal contribution

Received: November 11, 2018       Accepted: January 14, 2019       Published: January 27, 2019
How to Cite

Copyright: © 2019 Müller-Durovic et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


CMV: Cytomegalovirus; DDR: DNA damage response; DMSO: Dimethyl sulfoxide; DSB: DNA double strand break; EBV: Epstein-Barr virus; Eomes: Eomesodermin; FACS: Fluorescence-activated cell sorting; FCS: Fetal calf serum; gMFI: Geometric mean fluorescence intensity; HD: Healthy donor; IFN-γ: Interferon-gamma; ILC: Innate lymphoid cell; IRP: Immune risk profile; KIR: Killer-cell immunoglobulin-like receptor; NCR: Natural cytotoxicity receptor; PBMCs: Peripheral blood mononuclear cells; TAF: Telomere-associated fluorescence; T-bet: T-box transcription factor; TNF-α: Tumor necrosis factor alpha.