Human Cytomegalovirus Infection of M1 and M2 Macrophages Triggers Inflammation and Autologous T-Cell Proliferation

Macrophages (M phi) are first targets during human cytomegalovirus (HCMV) infection and are thought to be crucial for viral persistence and dissemination. However, since M phi are also a first line of defense and key modulators of the immune response, these cells are at the crossroad between protection and viral pathogenesis. To date, the M phi-specific contribution to the immune response against HCMV is still poorly understood. In view of the opposite roles of M1 and M2 M phi during initiation and resolution of the immune response, we characterized the effects of HCMV infection on classically activated M1 M phi and alternatively activated M2 M phi. Although HCMV susceptibility was higher in M2 M phi, HCMV established a productive and persistent infection in both types of M phi. Upon HCMV encounter, both types of M phi acquired similar features of classical activation and secreted high levels of proinflammatory cytokines and chemokines. As a functional consequence, conditioned media obtained from HCMV-infected M1 and M2 M phi potently activated freshly isolated monocytes. Finally, compared to HCMV-infected monocyte-derived dendritic cells, infected M1 and M2 M phi were more efficient in stimulating proliferation of autologous T cells from HCMV-seropositive donors at early times (24 h) postinfection, while the M phi immunostimulatory properties were reduced, but not abrogated, at later times (72 h postinfection). In summary, our findings indicate that M phi preserve proper antigen presentation capacity upon HCMV infection while enhancing inflammation, thus suggesting that M phi play a role in the maintenance of the large HCMV-specific T-cell repertoire in seropositive individuals.