Expansion of the NKG2C+ Natural Killer–Cell Subset Is Associated With High-Risk Carotid Atherosclerotic Plaques in Seropositive Patients for Human Cytomegalovirus

Abstract

Objective-Human cytomegalovirus (HCMV), a pathogen involved in the development and progression of atherosclerosis, promotes in some individuals a marked reconfiguration of the natural killer (NK)-cell compartment whose hallmark is a persistent expansion of a peripheral blood NK-cell subset expressing the CD94/NKG2C NK receptor. We aimed to evaluate whether the HCMV-associated NK-cell compartment reconfiguration is related to carotid atherosclerotic plaque (CAP) instability. Approach and Results-NK receptor expression (ie, LILRB1, NKG2A, NKG2C, and killer immunoglobulin-like receptors [KIR]) by peripheral NK and T cells was evaluated in 40 patients with HCMV+ with CAP, including nonatherosclerotic strokes (n=15) and healthy subjects (n=11) as controls. High-risk CAP (n=16), defined as carotid stenosis >50% with ipsilateral neurological symptomatology in the previous 180 days, compared with non-high-risk CAP had higher %NKG2C+ NK cells (29.5±22.4% versus 16.3±13.2%; P=0.026; odds ratio, 1.053; 95% confidence interval, 1.002-1.106; P=0.042), with a corresponding reduction in the NKG2A+ NK subset (31.7±17.8% versus 41.8±15.8%; P=0.072). The proportions of NKG2C+ NK cells in high-risk CAP were inversely correlated with the CD4+/CD8+ ratio (R Spearman =−0.629; P=0.009) and directly with high-sensitivity C-reactive protein levels (R Pearson =0.591; P=0.012), consistent with higher subclinical systemic inflammation. The intraplaque inflammatory infiltrate, evaluated in 27 CAP obtained after endarterectomy, showed a higher presence of subintimal CD3+ lymphocytes in those patients with HCMVinduced changes in the peripheral NK-and T-cell compartments. antibodies, which only partially reflect the complexity of the host-pathogen relationship. Conclusions-TheIn this context, herpesviruses may have a substantial effect in the progression of atherosclerosis and the cardiovascular risk.7 Among them, human cytomegalovirus (HCMV) is thought to be involved in the development of atherosclerosis based on clinico-epidemiological and experimental studies and has been proposed to contribute to the progression of the carotid plaque thickness 4 and the degree of stenosis. 8,9 In healthy individuals, HCMV remains latent, establishing a persistent infection and eventually undergoing subclinical reactivations. A remarkable fraction of the CD8+ T-cell compartment may be directed against HCMV, a phenomenon that has been associated with immunosenescence, leading in some aged healthy individuals to a reduction of the CD4+/CD8+ T-cell ratio. [10][11][12] In addition, HCMV has been shown to promote a persistent expansion of a peripheral blood NK-cell subset expressing high levels of the CD94/ NKG2C+ lectin-like receptor, 13 detectable to a variable degree in healthy subjects. 14 We hypothesize that the contribution of HCMV infection to atherosclerosis may depend on features of the host-pathogen relationship not reflected by the simple serological status. In the present study, the relationship of the HCMV-associated NK-cell compartment reconfig...

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

“…These cells have some characteristics of adaptive immunity and are considered “memory” or “adaptive” NK cells (55–58). The magnitude of the expansion of NKG2C high NK cells is determined by the magnitude of the proinflammatory cytokine secretion upon NK cell activation (59), and it has been proposed that these cells contribute to the proinflammatory environment based on the relation between the percentage of NKG2C + cells, elevated levels of PCR, and cardiovascular risk determinants of CMV-seropositive individuals (60, 61). …”

Carotid atherosclerosis, cytomegalovirus infection, and cognitive decline in the very old: a community-based prospective cohort study

“…Those with detectable CMV DNA had significantly higher percentages of CMVspecific CD8+ T cells than those without; nevertheless, levels of CMV IgG antibody were comparable among the two groups (Leng et al 2011). More recently, Enrique et al reported that in CMV seropositive patients, proportion of natural killer receptor NKG2C-positive cells, but not CMV antibody levels, were associated with higher carotid plaque burden, plaque instability, and high CRP levels but correlated with lower CD4/CD8 ratio (Martinez-Rodriguez et al 2013). Collectively, these results suggest that CMV antibody level may only reflect part of the complex host-pathogen interaction, and coexisting atherosclerosis could be a surrogate marker for persistent reactivation of this virus.…”

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

“…It is tempting to speculate that a systemic proinflammatory environment sustained by NKG2C bright NK cells could underlie the described association between the frequency of NKG2C + NK cells, elevated C-reactive protein levels, and high-risk carotid plaques in HCMV + patients (56).…”