TY - JOUR
T1 - Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation
AU - Chao, Ying-Yin
AU - Puhach, Alisa
AU - Frieser, David
AU - Arunkumar, Mahima
AU - Lehner, Laurens
AU - Seeholzer, Thomas
AU - Garcia-Lopez, Albert
AU - van der Wal, Marlot
AU - Fibi-Smetana, Silvia
AU - Dietschmann, Axel
AU - Sommermann, Thomas
AU - Ćiković, Tamara
AU - Taher, Leila
AU - Gresnigt, Mark S
AU - Vastert, Sebastiaan J
AU - van Wijk, Femke
AU - Panagiotou, Gianni
AU - Krappmann, Daniel
AU - Groß, Olaf
AU - Zielinski, Christina E
N1 - Funding Information:
We thank all past and present members of the Zielinski laboratory for fruitful discussions and technical support, in particular R. Noster, A. Burrell, F. Laudisi and S.-H. Park for technical and experimental help. We thank L. Richter and J. Klein (Core Facility Flow Cytometry, Biomedical Center, Munich) for support with imaging flow cytometry, M. Schmidt-Supprian for support with CRISPR–Cas9 gene editing and P. Wehner for support with live cell imaging analysis. This work was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) through grant no. SFB 1054 (project ID 210592381, to C.E.Z.), TRR/SFB 124 (project ID 210879364, to C.E.Z. and M.S.G.), Leibniz Center for Photonics in Infection Research (grant no. LPI-BT6, to C.E.Z.), GRK 2606 (project ID 423813989, to O.G.), Germany’s Excellence Strategy (Balance of the Microverse, to C.E.Z), Emmy Noether Program (project no. 434385622/GR 5617/1-1, to M.S.G.), the German Center of Infection Research (to C.E.Z.), Carl-Zeiss Stiftung (to C.E.Z.) and by the European Research Council (grant nos. 337689 and 966687, to O.G.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85145706150
U2 - 10.1038/s41590-022-01386-w
DO - 10.1038/s41590-022-01386-w
M3 - Article
C2 - 36604548
SN - 1529-2908
VL - 24
SP - 295
EP - 308
JO - Nature immunology
JF - Nature immunology
IS - 2
ER -