*,P< 0.05. cell-mediated control of HCMV transmission. Furthermore, the efficacy of the antibody-dependent NK cell-mediated control of HCMV transmission is dependent on a CD16-158V/F polymorphism. Our findings indicate that NK cells may have a clinical relevance in HCMV contamination Rabbit Polyclonal to PTPN22 and highlight the need to consider potential therapeutic strategies based on the manipulation of NK cells. IMPORTANCEHuman cytomegalovirus (HCMV) infects 40% to 100% of the human population worldwide. After primary contamination, mainly in childhood, the virus establishes a lifelong persistence with possible reactivations. Most infections remain asymptomatic; however, HCMV represents a major health problem since it is the most frequent cause of infection-induced birth defects and is responsible for high morbidity and mortality in immunocompromised patients. The immune system normally controls the infection by antibodies and immune effector cells. One type of effector cells are the natural killer (NK) cells, which provide a rapid response to virus-infected cells. NK cells participate in viral clearance by inducing the death of infected cells. NK cells also secrete antiviral cytokines as a consequence of the conversation with an infected cell. In this study, we investigated the mechanisms by which NK cells control HCMV transmission, from the perspectives of immune surveillance and immune evasion. == INTRODUCTION == Human cytomegalovirus (HCMV) is an enveloped virus that belongs to the familyHerpesviridae. HCMV remains the most important viral pathogen in severely immunocompromised individuals, with substantial morbidity and mortality. It is also the major cause of congenital infections that lead to developmental abnormalities and fetal death (1). Following initial contamination, HCMV Resiniferatoxin transmission can occur in cell cultures either by cell-free virus through the supernatant or by cell-to-cell transmission involving direct cell contact (2). In clinical practice, HCMV detection by isolation in cell cultures, pp65 antigenemia, and detection of viral DNA from blood (DNAemia) are used to diagnose an active systemic HCMV contamination. Fromin vitrodata, it can be concluded that antigenemia requires cell-to-cell contact between infected cells and polymorphonuclear leukocytes (PMN), which allows PMNs to load with viral antigens, mainly pp65 (3). Although the mechanisms of HCMV cell-to-cell transmission are not fully clear, many authors hypothesized that this mode is more importantin vivo. This is also supported by the fact that most clinical HCMV isolates spread strictly from cell to cell in fibroblast cultures at low passage numbers (4). During contamination, HCMV encounters the host immune defense mechanisms, including intrinsic, innate, and adaptive immunity. The clinical outcome of HCMV contamination mainly depends on the antiviral immunity. As effectors of the innate immunity, NK cells provide a rapid response to virus-infected cells (5). The most prominent functions of NK cells are their ability to produce antiviral cytokines and lyse virus-infected cells. NK cells can be activated by HCMV-infected cells (6,7), and they are supposed to be important for the protection against HCMV infectionsin vivo. A case report indicated that NK cell deficiency was associated with severe herpesvirus infections, including active HCMV Resiniferatoxin contamination confirmed by virus isolation (8). Another case report showed that NK cell expansion was correlated with the control Resiniferatoxin of an HCMV contamination in the absence of T cells in a TBNK+SCID patient (9). Furthermore, HCMV is the only virus known that can shape the human NK cell’s receptor repertoire (10,11). These clues highly suggest a role of NK cells in the defense against HCMV contamination; however, direct proof of NK cells in controlling HCMV contamination is absent. By using an improved focus expansion assay (4,12), we used a systematic approach to investigate the contribution of NK cells to HCMV transmission. We characterized HCMV transmission in various cell types and the NK cell contribution in controlling HCMV transmission. The assay we developed not only provides a clinically relevant readout for determination of the immune cell function in HCMV research, but will also allow other researchers to study the role of immune cells in other viral infections. == MATERIALS.