Natural killer (NK) cells and CD8 ؉ T cells play a prominent role in the clearance of mouse cytomegalovirus (MCMV) infection.The role of NK cells in modulating the CD8 ؉ T-cell response to MCMV infection is still the subject of intensive research. For analyzing the impact of NK cells on mounting of a CD8 ؉ T-cell response and the contribution of these cells to virus control during the first days postinfection (p.i.), we used C57BL/6 mice in which NK cells are specifically activated through the Ly49H receptor engaged by the MCMV-encoded ligand m157. Our results indicate that the requirement for CD8 ؉ T cells in early MCMV control inversely correlates with the engagement of Ly49H. While depletion of CD8 ؉ T cells has only a minor effect on the early control of wild-type MCMV, CD8 ؉ T cells are essential in the control of ⌬m157 virus. The frequencies of virus epitope-specific CD8 ؉ T cells and their activation status were higher in mice infected with ⌬m157 virus. In addition, these mice showed elevated levels of alpha interferon (IFN-␣) and several other proinflammatory cytokines as early as 1.5 days p.i. Although the numbers of conventional dendritic cells (cDCs) were reduced later during infection, particularly in ⌬m157-infected mice, they were not significantly affected at the peak of the cytokine response. Altogether, we concluded that increased antigen load, preservation of early cDCs' function, and higher levels of innate cytokines collectively account for an enhanced CD8 ؉ T-cell response in C57BL/6 mice infected with a virus unable to activate NK cells via the Ly49H-m157 interaction. Mouse cytomegalovirus (MCMV) has been extensively used as a model for studying the role of NK cells in virus control. NK cells play a crucial role in the early stage of MCMV infection, prior to the induction of the adaptive immune response (20). However, the contribution of NK cells in the control of early MCMV infection varies among mouse strains (38; reviewed in reference 43). In C57BL/6 mice, the activating NK cell receptor Ly49H mediates resistance to MCMV infection due to the specific binding of m157, a virally encoded protein (6, 46). NK cell activation through Ly49H-m157 interaction is characterized by perforin-mediated cytotoxicity and specific proliferation of Ly49H ϩ NK cells (13,26,49). Unlike C57BL/6 mice, MCMV-susceptible mouse strains are unable to mount an effective NK cell response to this virus (reviewed in reference 42).In addition to their direct function, which results in the containment of viral infection, a large body of accumulated data suggests that NK cells play a role also in the shaping of the specific immune response (reviewed in reference 50). However, this topic is still controversial and the subject of intense studies. Robbins and colleagues (40) have shown that NK cell activation via the Ly49H-m157 pathway accelerates the CD8 ϩ T-cell response in vivo. According to the proposed scenario, the activation of NK cells via this axis limits alpha/beta interferon (IFN-␣/␤) production by plasmacytoid den...

Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination.

Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well-established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8 T cells in the brain following infection of newborn mice. We show that CD8 T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T cells) that persist for lifetime. Adoptively transferred virus-specific CD8 T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as T cells. Brain CD8 T cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8 T cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.