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

doi:10.1038/s41590-022-01386-w

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

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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 language	English
Pages (from-to)	295-308
Number of pages	14
Journal	Nature immunology
Volume	24
Issue number	2
Early online date	5 Jan 2023
DOIs	https://doi.org/10.1038/s41590-022-01386-w
Publication status	Published - Feb 2023

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Chao, Y.-Y., 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, M. S., Vastert, S. J., van Wijk, F., Panagiotou, G., Krappmann, D., Groß, O., & Zielinski, C. E. (2023). Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation. Nature immunology, 24(2), 295-308. https://doi.org/10.1038/s41590-022-01386-w

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

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.",

author = "Ying-Yin Chao and Alisa Puhach and David Frieser and Mahima Arunkumar and Laurens Lehner and Thomas Seeholzer and Albert Garcia-Lopez and {van der Wal}, Marlot and Silvia Fibi-Smetana and Axel Dietschmann and Thomas Sommermann and Tamara {\'C}ikovi{\'c} and Leila Taher and Gresnigt, {Mark S} and Vastert, {Sebastiaan J} and {van Wijk}, Femke and Gianni Panagiotou and Daniel Krappmann and Olaf Gro{\ss} and Zielinski, {Christina E}",

note = "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{\textquoteright}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: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = feb,

doi = "10.1038/s41590-022-01386-w",

language = "English",

volume = "24",

pages = "295--308",

journal = "Nature immunology",

issn = "1529-2908",

publisher = "Nature Research",

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Chao, Y-Y, 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', Nature immunology, vol. 24, no. 2, pp. 295-308. https://doi.org/10.1038/s41590-022-01386-w

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.

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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 -

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

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