Human Th17 cells engage gasdermin E pores to release IL-1a upon NLRP3 inflammasome activation

There is evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here, we found that human T cells expressed gasdermin E (GSDME), a membrane pore-forming molecule that has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunneled release of the alarmin IL-1a. This property was restricted to a subset of human Th17 cells with specificity for C. albicans and was regulated by a T cell-intrinsic NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T-cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL1a form. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This finding diversifies the functional repertoire and mechanistic equipment of T cells with implications for anti-fungal host defense.