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

Abstract

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.

Beyond Uterine Natural Killer Cell Numbers in Unexplained Recurrent Pregnancy Loss: Combined Analysis of CD45, CD56, CD16, CD57, and CD138

“…Reduced numbers of uNK cells were reported in the endometrium of RPL patients infected with the human herpesvirus 6 (HHV6) [62]. The expansion of singular CD56 neg CD16 + cells with altered functions can be promoted by viruses, including hepatitis C and cytomegalovirus (CMV) [63][64][65]. Differently from other subgroups, the uRPL-CD56 high subgroup presented a low proportion of CD57 + compared to CD56 + cells.…”

The incidence of cytomegalovirus infection after deceased-donor kidney transplantation from hepatitis-C antibody positive donors to hepatitis-C antibody negative recipients

“…Some studies have not corroborated this association and exact mechanisms have not been well known, but CMV may confer an immunomodulatory effect via indirect effects and dysregulate specific cytokines against HCV replication [ 22 ]. Indeed, HCV infection per se can also promote conditions that are likely to reactivate both BK [ 14 ] and CMV infections via several mechanisms [ 15 , 16 ]. Chronic viral infections such as HCV and HIV alter natural killer (NK) cell subsets and impair the defensive ability against viral infections, including CMV [ 15 , 16 ].…”

“…Indeed, HCV infection per se can also promote conditions that are likely to reactivate both BK [ 14 ] and CMV infections via several mechanisms [ 15 , 16 ]. Chronic viral infections such as HCV and HIV alter natural killer (NK) cell subsets and impair the defensive ability against viral infections, including CMV [ 15 , 16 ].…”

“…However, it is not known whether HCV infection directly stimulates CMV reactivation/infection or contributes to immunosuppression. Indeed, HCV viral replication might theoretically create a milieu for secondary viral infections by enhancing pro-inflammatory and profibrotic processes in BK virus infection [14] and by the modification of the natural killer (NK) cells' subset in CMV infection [15,16]. In real-world experience, the approval of DAA by a third-party payer may take a considerable amount of time, that is, our former study reported a median duration of 76 days for starting DAA after KT [4].…”

A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases

“…CD56 neg CD16 pos NK cells were discovered 25 years ago in Human Immunodeficiency Virus (HIV) patients (Hu et al, 1995) and has been shown to expand during other chronic infections, such as Hepatitis C Virus (HCV), especially those who failed treatment (Mavilio et al, 2003(Mavilio et al, , 2005Gonzalez et al, 2009;Prada et al, 2013) and more recently in human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) co-infected elderly individuals (>60 years of age) (Müller-Durovic et al, 2019). Compared to CD56 pos NK cells, CD56 neg NK cells have been portrayed as "dysfunctional" because of lower expression of cytotoxic receptors such as NKp46 and NKp30, low cytokine production as well as reduction of natural cytotoxicity (Mavilio et al, 2005;Müller-Durovic et al, 2019). More recently, we reported a dramatic expansion of CD56 neg CD16 pos NK cells in African children chronically/repeatedly infected with Plasmodium falciparum malaria and in those who were diagnosed with endemic Burkitt lymphoma (eBL) (Forconi et al, 2018).…”