Brief Report IMMUNOBIOLOGY CpG pretreatment enhances antiviral T-cell immunity against cytomegalovirus

The generation of antigen-specific CD8 T-cell responses is integral to effective cell-mediated antiviral immunity. Indeed, the control of infections with many viral pathogens is highly dependent on the timely and successful priming of naive T cells by professional antigen-presenting cells (APCs). It has been widely reported, and is now generally accepted, that cross-presentation, namely the acquisition of exogenous antigen for reprocessing and presentation on major histocompatibility complex class I (MHC-I) molecules, is crucial for antiviral CD8 T-cell immunity. Cross-presentation allows dendritic cells (DCs) to initiate a response to pathogens that do not infect DCs, inactivate them, or eliminate them in the process of infection. Cytomegalovirus (CMV) has been studied in great detail with regard to the capacity to interfere with antigen presentation. Although CMV readily infects both DCs and macrophages, the principal APC populations, cross-presentation has been postulated to be critical for the generation of antiviral CD8 T-cell responses because the virus encodes several proteins that impair antigen presentation. However, the effects of these viral proteins may be limited, especially in vivo. Despite antiviral therapies, CMV still poses a significant clinical problem and remains the most predictable and problematic infection in bone marrow and solid organ transplantation, and a major health risk in immunocompromised patients generally. Most pathology associated with CMV infection is due to an inability to generate appropriate CD8 T-cell immunity; thus, a better understanding of the processes required to prime protective T-cell responses would be significant. Importantly, the critical question as to whether protective antiviral CD8 T-cell responses are elicited by cross-presentation has not been addressed. Here, we assessed the importance of direct vs cross-presentation in the development of antiviral T-cell immunity in a model of CMV infection where antiviral CD8 T-cell responses are essential for host survival.We used this system to analyze not only the development of antiviral CD8 T-cell immunity, but also whether the responses generated could afford protection. As such, this is the first study to define the role of direct vs cross-presentation in the generation of protective antiviral immunity to a clinically important viral pathogen.