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Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Author

Listed:
  • Michael Dudek

    (Technical University of Munich (TUM))

  • Dominik Pfister

    (German Cancer Research Center)

  • Sainitin Donakonda

    (Technical University of Munich (TUM)
    German Center for Infection Research)

  • Pamela Filpe

    (University Medical Centre Hamburg-Eppendorf)

  • Annika Schneider

    (Technical University of Munich (TUM))

  • Melanie Laschinger

    (University Hospital München rechts der Isar, TUM)

  • Daniel Hartmann

    (University Hospital München rechts der Isar, TUM)

  • Norbert Hüser

    (University Hospital München rechts der Isar, TUM)

  • Philippa Meiser

    (Technical University of Munich (TUM))

  • Felix Bayerl

    (Technical University of Munich (TUM))

  • Donato Inverso

    (German Cancer ResearchCenter Heidelberg (DKFZ-ZMBH Alliance)
    Heidelberg University)

  • Jennifer Wigger

    (University Medical Centre Hamburg-Eppendorf)

  • Marcial Sebode

    (University Medical Centre Hamburg-Eppendorf)

  • Rupert Öllinger

    (Institute of Molecular Oncology and Functional Genomics, TUM)

  • Roland Rad

    (Institute of Molecular Oncology and Functional Genomics, TUM)

  • Silke Hegenbarth

    (Technical University of Munich (TUM))

  • Martina Anton

    (Technical University of Munich (TUM))

  • Adrien Guillot

    (Charité Universitätsmedizin)

  • Andrew Bowman

    (Maastricht University)

  • Danijela Heide

    (German Cancer Research Center)

  • Florian Müller

    (German Cancer Research Center)

  • Pierluigi Ramadori

    (German Cancer Research Center)

  • Valentina Leone

    (Technical University Munich and Helmholtz Zentrum Munich
    Helmholtz Zentrum Munich)

  • Cristina Garcia-Caceres

    (Helmholtz Zentrum München)

  • Tim Gruber

    (Helmholtz Zentrum München)

  • Gabriel Seifert

    (University of Freiburg)

  • Agnieszka M. Kabat

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Jan-Philipp Mallm

    (German Cancer Research Center)

  • Simon Reider

    (Medical University Innsbruck
    Christian Doppler Labor for Mucosal Immunology)

  • Maria Effenberger

    (Medical University Innsbruck)

  • Susanne Roth

    (Heidelberg University)

  • Adrian T. Billeter

    (Heidelberg University)

  • Beat Müller-Stich

    (Heidelberg University)

  • Edward J. Pearce

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Friedrich Koch-Nolte

    (University Medical Center Hamburg-Eppendorf)

  • Rafael Käser

    (University of Freiburg)

  • Herbert Tilg

    (Medical University Innsbruck)

  • Robert Thimme

    (University of Freiburg)

  • Tobias Boettler

    (University of Freiburg)

  • Frank Tacke

    (Charité Universitätsmedizin)

  • Jean-Francois Dufour

    (University of Bern)

  • Dirk Haller

    (School of Life Sciences Weihenstephan, TUM)

  • Peter J. Murray

    (Technical University of Munich (TUM)
    Max Planck Institute for Biochemistry)

  • Ron Heeren

    (Maastricht University)

  • Dietmar Zehn

    (School of Life Sciences Weihenstephan, TUM)

  • Jan P. Böttcher

    (Technical University of Munich (TUM))

  • Mathias Heikenwälder

    (German Cancer Research Center)

  • Percy A. Knolle

    (Technical University of Munich (TUM)
    German Center for Infection Research
    School of Life Sciences Weihenstephan, TUM)

Abstract

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Suggested Citation

  • Michael Dudek & Dominik Pfister & Sainitin Donakonda & Pamela Filpe & Annika Schneider & Melanie Laschinger & Daniel Hartmann & Norbert Hüser & Philippa Meiser & Felix Bayerl & Donato Inverso & Jennif, 2021. "Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH," Nature, Nature, vol. 592(7854), pages 444-449, April.
    • Handle: RePEc:nat:nature:v:592:y:2021:i:7854:d:10.1038_s41586-021-03233-8
    DOI: 10.1038/s41586-021-03233-8
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    Cited by:

    1. Elizabeth Balint & Emily Feng & Elizabeth C. Giles & Tyrah M. Ritchie & Alexander S. Qian & Fatemeh Vahedi & Amelia Montemarano & Ana L. Portillo & Jonathan K. Monteiro & Bernardo L. Trigatti & Ali A., 2024. "Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Hao-Xian Zhu & Shu-Han Yang & Cai-Yue Gao & Zhen-Hua Bian & Xiao-Min Chen & Rong-Rong Huang & Qian-Li Meng & Xin Li & Haosheng Jin & Koichi Tsuneyama & Ying Han & Liang Li & Zhi-Bin Zhao & M. Eric Ger, 2024. "Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Caihua Zhang & Kang Li & Hongzhang Zhu & Maosheng Cheng & Shuang Chen & Rongsong Ling & Cheng Wang & Demeng Chen, 2024. "ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    4. Paul Little & Si Liu & Vasyl Zhabotynsky & Yun Li & Dan-Yu Lin & Wei Sun, 2023. "A computational method for cell type-specific expression quantitative trait loci mapping using bulk RNA-seq data," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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