Gene expression profile of human Th17 cells

Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging 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 show that human T cells can express gasdermin E (GSDME), a membrane pore forming molecule, which 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 tunnelled release of the calpain-matured innate danger signal IL-1a. This property was restricted to a subset of human Th17 cells and regulated by the NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T cell receptor stimulation. Autocrine IL-1a signaling enforced a pro-inflammatory Th17 cell fate through continuous IL-10 suppression and showed an association of this T cell subset with the autoinflammatory Schnitzler syndrome. 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 diversifies the functional repertoire and mechanistic equipment of T cells and thus provides new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in various diseases. A library of human Th17 cells that were sorted ex vivo as CCR6+CCR4+CXCR3– memory Th cells using fluorescence-activated cell sorting (FACS) and then stimulated with anti-CD3 and anti-CD28 mAbs for 4 days (2 days plate-bound).