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

Chao YY, Puhach A, Frieser D, Arunkumar M, Lehner L, Seeholzer T, Garcia-Lopez A, van der Wal M, Fibi-Smetana S, Dietschmann A, Sommermann T, Ćiković T, Taher L, Gresnigt MS, Vastert SJ, van Wijk F, Panagiotou G, Krappmann D, Groß O, Zielinski CE (2023) Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation. Nat Immunol 24(2), 295-308.


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.


Mahima Arunkumar
Ying-Yin Chao
Axel Dietschmann
Albert García López
Mark Gresnigt
Laurens Lehner
Gianni Panagiotou
Alisa Puhach
Christina Zielinski


doi: 10.1038/s41590-022-01386-w

PMID: 36604548