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

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

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  • Media type: E-Article
  • Title: Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation
  • Contributor: Chao, Ying-Yin; Puhach, Alisa; Frieser, David; Arunkumar, Mahima; Lehner, Laurens; Seeholzer, Thomas; Garcia-Lopez, Albert; van der Wal, Marlot; Fibi-Smetana, Silvia; Dietschmann, Axel; Sommermann, Thomas; Ćiković, Tamara; Taher, Leila; Gresnigt, Mark S.; Vastert, Sebastiaan J.; van Wijk, Femke; Panagiotou, Gianni; Krappmann, Daniel; Groß, Olaf; Zielinski, Christina E.
  • Published: Springer Science and Business Media LLC, 2023
  • Published in: Nature Immunology, 24 (2023) 2, Seite 295-308
  • Language: English
  • DOI: 10.1038/s41590-022-01386-w
  • ISSN: 1529-2908; 1529-2916
  • Origination:
  • Footnote:
  • Description: AbstractIt 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.