Role of "Memory-like" Natural Killer cells in Human Cytomegalovirus seropositive atherosclerotic patients

Background: Human Cytomegalovirus (HCMV) is a DNA virus that remains latent in host cells upon primary infection. HCMV can infect a broad range of host cells, including monocytes/macrophages. Recent work has shown that seropositive individuals have a varied distribution of HCMV in different tissues; and curiously HCMV nucleic acids and/or antigens have also been detected in atherosclerotic plaques. In this context, HCMV has been proposed to possibly contribute to the progression of the carotid atherosclerotic plaque (CAP). Natural Killer cells (NK cells) are a subpopulation of innate lymphoid cells (ILC-1) which play a crucial role in the innate response against viruses and intracellular bacteria, as HCMV . In CAP of pts with cerebrovascular symptoms has been demonstrated the presence of activated NK cells, stronger producers of IFN-γ, cytokine involved in plaque destabilization. Remarkably, in individual infected by HCMV have been identified “memory-like or adaptive” NK cells, a subset of NK cells characterized by adaptive immune features, including long-term persistence, unique epigenetic profile, and enhanced functional responsiveness in terms of IFN- γ production. Purpose: Having regard as reported, we hypothesize that HCMV infection/reactivation, which could occur in potential virus repositories present in plaque, may induces an innate immune response able to impair the stability of plaque. More specifically, we propose that HCMV infection may triggers the activation of memory-like NK cells. This compartment of NK cells, virus induced, have strong CD16-mediated effector functions (Antibody-dependent cellular cytotoxicity, ADCC), in terms of IFN- 𝛾 release, cytokines involved in plaque destabilization. Results: In our cohort of atherosclerotic patients, NK cells from HCMV seropositive patients had enhanced CD16-mediated IFN-γ release when compared to both low-risk HCMV+ pts, and all HCMV- pts. The amplify production of IFN-g was directly correlated to the frequency of CD56dim FcεR1γ- NK cells. Therefore, FcεR1γ- memory-like NK cells subset, from HCMV+ patients, was significantly expressed in the peripheral blood (PB) of high-risk patients compared to low-risk. Remarkably, NKG2C- FcεR1γ- adaptive NK cells were suggestively increased in PB of high-risk pts compared to low-risk and this subpopulation also appear incremented in CAP of high-risk pts compared to their autologous PB. Moreover, this specific subset of NK cells seemed to expand in some pts in follow-up, evolved over time. Interesting, immunohistochemical analyses revealed that NK cells (NKp46+ cells) and macrophagic cells (CD68+ cells) infiltrate the atheromatous plaque and, HCMV is localized intimate the CAP inside macrophage-like cells. Conclusions: All together our data suggest the importance of investigating the presence of HCMV in atherosclerotic pts, as well as detecting in the same pts specific subsets of memory- like NK cells, virus- induced. Both could become potential markers to identify low-risk pts who, having similar profile to high-risk pts, may suffer from plaque destabilization and subsequent negative outcomes.