NK cells undergo transcriptional and functional reprogramming following Streptococcus pneumoniae infection

Natural Killer (NK) cells are cytotoxic lymphocytes and key mediators of innate immunity, essential for combating viral infections and cancer. Notably, they exhibit immunological memory, generating a stronger response upon re-exposure to the same stimulus. While NK cell memory holds promise for infection control, its role in bacterial infections remains poorly understood. Previously, we demonstrated that Streptococcus pneumoniae induces long-term, specific, and protective NK cell memory. In this study, we performed single-cell RNA-seq to uncover how NK cells respond to S. pneumoniae infection. Our findings reveal that challenged Memory (cMemory) NK cells undergo transcriptional reprogramming following S. pneumoniae infection and have a differential transcriptional response upon reinfection. In addition, we identified distinct cMemory NK cell subpopulations, with responding cMemory NK cells displaying a general enhanced activation, proliferation, and cytotoxic activity. These findings support a novel role for NK cells in the context of bacterial infections, thereby opening avenues for harnessing the potential of innate immune memory for therapeutic applications.