Inflammasome-Dependent Induction of Adaptive NK Cell Memory

Monobenzone is a pro-hapten that is exclusively metabolized by melanocytes, thereby haptenizing melanocyte-specific antigens, which results in cytotoxic autoimmunity specifically against pigmented cells. Studying monobenzone in a setting of contact hypersensitivity (CHS), we observed that monobenzone induced a long-lasting, melanocyte-specific immune response that was dependent on NK cells, yet fully intact in the absence of T- and B cells. Consistent with the concept of “memory NK cells,” monobenzone-induced NK cells resided in the liver and transfer of these cells conferred melanocyte-specific immunity to naive animals. Monobenzone-exposed skin displayed macrophage infiltration and cutaneous lymph nodes showed an inflammasome-dependent influx of macrophages with a tissue-resident phenotype, coinciding with local NK cell activation. Indeed, macrophage depletion or the absence of the NLRP3 inflammasome, the adaptor protein ASC or interleukin-18 (IL-18) abolished monobenzone CHS, thereby establishing a non-redundant role for the NLRP3 inflammasome as a critical proinflammatory checkpoint in the induction of hapten-dependent memory NK cells. •The melanocyte-dependent hapten monobenzone triggers contact hypersensitivity (CHS)•Monobenzone-induced CHS is mediated by memory NK cells that target melanocytes•NK cell CHS memory requires the NLRP3 inflammasome in tissue-resident macrophages Natural killer cells can acquire properties that are consistent with features of immunological memory. Hornung and colleagues show that the contact-sensitizer monobenzone induces pigment cell-specific memory NK cells, while the NLRP3 inflammasome serves as a critical and non-redundant proinflammatory checkpoint in the formation of this memory NK cell response.