Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation

Nat Immunol. 2023 Feb;24(2):295-308. doi: 10.1038/s41590-022-01386-w. Epub 2023 Jan 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 1 / metabolism
  • Gasdermins
  • Humans
  • Immunity, Innate
  • Inflammasomes* / metabolism
  • Interleukin-1beta / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Pyroptosis
  • Th17 Cells*


  • Caspase 1
  • Gasdermins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein