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

Date Published: January 31, 2019

Publisher: Impact Journals

Author(s): Bojana Müller-Durovic, Jasmin Grählert, Oliver P. Devine, Arne N. Akbar, Christoph Hess.


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.

Partial Text

CMV and EBV are the most ubiquitous herpes viruses, with a prevalence of up to 95% for EBV and close to 50% for CMV in the adult Western population [1]. Following primary infection, most often during early life, both viruses establish life-long latent infection. While immune-competent hosts are mostly asymptomatic, CMV and EBV can cause illness in immune-compromised individuals. Importantly, CMV is known to significantly shape the immune system with increasing age. Specifically, inflation of CMV-specific CD8+ T cells with a terminally differentiated phenotype (CD8+CD28–) and an inverted CD4 / CD8 T cell ratio have been described in CMV-positive individuals [2,3].

In a cohort of healthy donors >60 years of age, we show that CD56neg NK cells expanded in CMV / EBV co-infection and that their frequency correlated with the immune risk profile (IRP). CD56neg NK cells were less functional when compared to CD56dim cells of the same donor in terms of their degranulation, killing capacity and IFN-γ production when stimulated with K562 target cells or IL-12 / IL-18, a feature that was more pronounced in CD56neg NK cells from CMV+EBV+ donors. Phenotypically CD56neg NK cells were mature cells, yet compared to CD56dim NK cells they were characterized by a CD57lowKIRlow phenotype, reduced T-bet expression and had longer telomeres compared to CD56dim NK cells. CD56neg NK cells thus distinguished themselves from CD56dim cells, the main effector population, as a distinct cell subset. Neither reduced expression of activating NK cell receptors, nor increased expression of PD-1 and TIM-3 accounted for reduced functionality of CD56neg NK cells. Likewise, no cell senescence characteristics were detected in this cell subset. In all, our data suggest that CD56neg NK cells can be viewed as an additional marker of immune risk in the aging host, and that EBV has a previously unrecognized role in immune senescence.




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