The pursuit of better vaccines: uncovering the functional capacity of human cytomegalovirus-induced subsets of NK cells

Abstract

Abstract Cytomegalovirus infection (CMV) poses a considerable burden to public health due to significant morbidity and mortality in immunocompromised patients and babies born with the infection, thus highlighting the priority of developing a successful CMV vaccine. Whereas previous CMV vaccination strategies have aimed to induce T- and B-cell responses, we speculate that natural killer (NK) cells hold the key to protective immunity based on the evidence that patients lacking NK cells suffer recurrent, severe infections with multiple herpesviruses, including CMV. Notably, CMV infections in both mice and humans triggered accumulation of unique adaptive NK-cell subsets that putatively possess enhanced effector functions against CMV. This suggests that a pioneering approach to creating an efficacious CMV vaccine would include stimulation of the accumulation and long-term maintenance of these CMV-reactive NK cells. It remains unknown, however, whether vaccines can be designed to stimulate the expansion of these NK-cell subsets. Here, using a unique set of samples collected during a CMV vaccine trial, we aim to determine whether vaccination promotes accumulation of these NK cells. Moreover, we examined the relationship between the activity of NK cells and stimulation of virus-specific T and B cell responses during immunization and in cell culture. Preliminary analysis revealed a supportive role for NK cells in stimulation of CMV-specific T cells during in vitro culture with peptide which correlates to the presence of adaptive NK cells. Our studies represent a key step in understanding the potential role of subsets of human NK cells in primary CMV infection and vaccine-induced immune responses against CMV.