Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation, 2023, Chao et al

"It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity."

"Cumulatively, our findings pave the way for a systematic investigation of the contributions of IL-1α-producing TH17 cells in various inflammatory diseases and antifungal host defense. The TCR–NLRP3 inflammasome–caspase-8–caspase-3–GSDME axis not only represents a previously overlooked mode of immune signaling and fate instruction in TH cells but also provides molecular targets to either disrupt a pathogenic TH17 cell identity or to harness it for host defense."

 

Link: https://www.nature.com/articles/s41590-022-01386-w