Non-canonical inflammasome drives intrinsic anti-microbial responses in human Natural Killer cells

Inflammasomes are critical in rapidly responding to infections and tissue damage, with current paradigms centred on macrophages and epithelial cells. Natural Killer (NK) cells are innate lymphoid cells essential for infection and sepsis, and are an important focus for cell-based immunotherapy. Inflammasome-derived cytokines control their activity however, potential intrinsic inflammasome functions remain unknown in these cells. Here, we use Salmonella enterica Typhimurium to show that human NK cells sense infection via the non-canonical inflammasome (NCI), triggering pyroptosis and interleukin (IL)-18 secretion, without canonical inflammasome activation. Interestingly, the NK non-canonical inflammasome can be primed by IL-12 but not interferon-γ, distinguishing it from the interferon-primed NCI in other cell types. In addition, although Salmonella infection in NK cells reduces over time, we identify persistent infection in a proportion of these cells. Furthermore, we see an inflammasome-dependent enhanced responsiveness to reinfection, suggesting a long-term impact of the inflammasome on NK cells. Overall, the NCI is specialised and distinct in human NK cells.