Expression of NKp30, NKp46 and DNAM-1 activating receptors on resting and IL-2 activated NK cells from healthy donors according to CMV-serostatus and age

Abstract

Human natural killer (NK) cells are innate lymphoid cells with capacity to kill tumor cells and virus-infected cells. According to the expression of CD56 and CD16 several NK cell subsets have been identified, a major CD56dimCD16+ subpopulation characterized by higher cytotoxic capacity, two CD56bright subsets (CD16-and CD16+) that represent different maturation stages and the fourth CD56-CD16+ subset that correspond to activated dysfunctional NK cells. Previous studies have shown quantitative changes in the frequency, phenotype and distribution of NK cell subsets depending on CMV-serostatus and age. We have analyzed the expression of NKp30, NKp46 and DNAM-1 NK activating receptors on resting and IL-2 activated NK cells from CMV-seronegative and seropositive healthy young donors and from CMV-seropositive elderly individuals. Our results showed that CMV-serostatus of healthy young donors is associated with phenotypic differences on both CD56bright and CD56dim NK cells with an increase of NKp46 and a decrease of NKp30 expression respectively. A reduced expression of DNAM-1 related to ageing and a lower NKp30 expression associated with CMV-seropositivity were observed. The expression of NKp46 and NKp30 was lower in CD57+ NK cells while the expression of DNAM-1 was increased. In vitro NK cell activation by IL-2 increased the expression of NKp46 and NKp30. In summary, both age and CMV-serostatus influence the expression of these cytotoxicity activating receptors that will have functional consequences. In elderly donors is difficult to isolate age from the effect of chronic CMV infection since in our study all elderly donors were CMV-seropositive. The possibility of modulating the expression of these activating receptors by cytokines such as IL-2 may open new opportunities for improving age-associated deterioration of NK cell function.

Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets

“…Thus, whereas different studies have shown an age-associated increased expression of KIR (20, 62) and a decreased expression of NKG2A (20), others have not found significant differences in the expression of KIR or NKG2A in the elderly (14, 17, 18, 30) or even a decreased expression of KIR (CD158a) in middle age donors if they are CMV-seropositive (63). The expression of another inhibitory receptor KLRG-1 is significantly reduced with aging (21) and with CMV seropositivity in the young individuals (63).…”

“…The expansion of CD57 + CD56 dim NK cells support previous data showing that acute and latent CMV infection leads to the expansion of CD57 + CD56 dim NK cells that also express NKG2C + (28, 49–54). CMV seropositivity is also associated with a decreased expression of other NK receptors, in some cases, as a consequence of the shift of NK cells to the more differentiated NKG2C + CD57 + phenotype (14, 27, 30, 54). These cells have some characteristics of adaptive immunity and are considered “memory” or “adaptive” NK cells (55–58).…”

“…Recent studies stratifying donors according to CMV serology have shown that increase of CD57 expression on CD56 dim NK cells is related to CMV seropositivity rather than aging (14) as well as the decreased expression of other surface receptors of NK cells, such as NKp30 (30) or CD161 (31). Thus, aging is associated with a loss of CD56 bright NK cell subpopulation (probably due to a decrease in the production of new NK cells in the bone marrow) and an expansion of memory-like NK cells CD56 dim CD57 + NKG2C + that is mainly related to CMV seropositivity [reviewed in Ref.…”

Facing challenges in an ageing world

“…Several original research articles included in this special issue present different aspects of the activity of antioxidants or bioactive compounds in blood (Jansen et al 2015;Capeleto et al 2015), the gender importance in fat accumulation during ageing (Castillo et al 2015), and the importance of the immune system during ageing (Campos et al 2015;Di Benedetto et al 2015).…”

“…Two papers included in this issue show different aspects of the evolution of the immune system during ageing. Rafael Solana's group from Córdoba, Spain, studies the expression of different natural killer (NK) activating receptors in the different NK cell subsets in order to understand the deterioration of these cells during ageing (Campos et al 2015). Graham Pawelec's group from Tübingen, Germany, discusses the impact of age, sex and CMV-infection on T cells (Di Benedetto et al 2015).…”