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

Ying-Yin Chao, Alisa Puhach, David Frieser, Mahima Arunkumar, Laurens Lehner, Thomas Seeholzer, Albert Garcia-Lopez, Marlot van der Wal, Silvia Fibi-Smetana, Axel Dietschmann, Thomas Sommermann, Tamara Ćiković, Leila Taher, Mark S Gresnigt, Sebastiaan J Vastert, Femke van Wijk, Gianni Panagiotou, Daniel Krappmann, Olaf Groß, Christina E Zielinski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Number of pages33
JournalNature Immunology
Early online date5 Jan 2023
DOIs
Publication statusE-pub ahead of print - 5 Jan 2023

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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