Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections

Abstract

Cytomegalovirus (CMV) infections may affect natural killer (NK) cells and are implicated in age‐related disorders—notably poor vascular endothelial function. Changes may be greater in renal transplant recipients (RTR) as they have a high burden of CMV and may influence antibody‐dependent cellular cytotoxicity (ADCC) responses to viral antigen. We obtained blood mononuclear cells from RTR stable after transplantation (n = 27) and age‐ and sex‐matched controls (n = 28). Natural killer (NK) cells were assessed for expression of CD107a or TNF‐α, after stimulation with autologous antibodies bound to CMV glycoprotein B (measuring ADCC) or anti‐CD16 (measuring NK cell activation). Alleles of FCRG3A (encoding CD16; rs396991) were determined by the Taqman assay. The vascular endothelial function was assessed using flow‐mediated dilatation (FMD) of the brachial artery. Proportions of NK cells expressing CD16 ex vivo were lower in RTR. Frequencies of NK cells expressing NKG2C or LIR‐1 or lacking FcRγ were highest in CMV‐seropositive RTR. ADCC was affected by rs396991 genotype and CMV gB antibody levels, but not by RTR status or detection of CMV DNA in plasma. Responses of FcRγ‐NK cells to anti‐CD16 were lower compared to FcRγ+ NK cells. Increased percentages of LIR‐1 + and FcRγ− NK cells correlated with lower FMD. In summary, CMV evokes substantial and similar ADCC responses in CMV seropositive RTR and controls. The equivalence may reflect higher titers of CMV reactive antibody in RTR, as NK responses stimulated by ligation of CD16 were lower. NK cells that were LIR‐1 + and/or FcRγ− were induced by CMV and correlated inversely with vascular endothelial function.

Challenging the Conventional Interpretation of HCMV Seronegativity

“…Neither IgA, IgG and IgM antibodies reactive with HCMV antigens nor HCMV vIL-10 were detectable in saliva or plasma (Table 1; data not shown). Analysis of her PBMC by flow cytometry revealed expanded populations of FcγRand NKG2C + NK-cells, characteristic of HCMV infection [17,18] (Table 1). The FcγRpopulation comprised 27.3% of CD3 -CD56 dim NK-cells, compared with a median (range) of 9.1 (5.4-19.1)% for other seronegative healthy controls (Figure 1).…”

“…Results were presented as arbitrary units (AU)/mL based on a standard plasma pool [13,14]. FcRγand NKG2C + NK cells (CD3 -CD56 dim ) and Vδ2-γδ T-cells were enumerated using multicolor flow cytometry, as the populations are expanded in CMV-seropositive RTR [18,19]. Enzyme linked immunosorbent spot (ELISpot) assays utilized anti-IFN antibodies (MabTech, Stockholm, Sweden).…”

Cytomegalovirus genotype distribution among postnatally infected infants: association of glycoprotein B, glycoprotein N and glycoprotein H types with CMV-associated thrombocytopenia

“…It has been reported that the gB genotypes vary in their ability to stimulate cell-mediated or cytotoxic immune response. 10 , 11 Therefore, variations in gB are likely to have significant effects on the pathogenesis of CMV disease and the spectrum of host cells infected by the virus. Our previous studies also confirmed that the gB1 genotype had more virulence in infants with symptomatic CMV disease.…”

Challenging the Conventional Interpretation of HCMV Seronegativity

“…Results were presented as arbitrary units (AU)/mL based on a standard plasma pool [14]. FcRγ − and NKG2C + NK cells (CD3 − CD56 dim ) and Vδ2 − γδ T-cells were enumerated using multicolour flow cytometry, as the populations are expanded in CMV-seropositive RTR [18,19]. Gating strategies are illustrated in Figure 1 and Supplementary Materials Figure S1.…”