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

Michael Dudek; Dominik Pfister; Sainitin Donakonda; Pamela Filpe; Annika Schneider; Melanie Laschinger; Daniel Hartmann; Norbert Hueser; Philippa Meiser; Felix Bayerl; Donato Inverso; Jennifer Wigger; Marcial Sebode; Rupert Oellinger; Roland Rad; Silke Hegenbarth; Martina Anton; Adrien Guillot; Andrew Bowman; Danijela Heide; Florian Mueller; Pierluigi Ramadori; Valentina Leone; Cristina Garcia-Caceres; Tim Gruber; Gabriel Seifert; Agnieszka M. Kabat; Jan-Philipp Malm; Simon Reider; Maria Effenberger; Susanne Roth; Adrian T. Billeter; Beat Mueller-Stich; Edward J. Pearce; Friedrich Koch-Nolte; Rafael Kaeser; Herbert Tilg; Robert Thimme; Tobias Boettler; Frank Tacke; Jean-Francois Dufour; Dirk Haller; Peter J. Murray; Ron Heeren; Dietmar Zehn; Jan P. Boettcher; Mathias Heikenwaelder; Percy A. Knolle

doi:10.1038/s41586-021-03233-8

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

Michael Dudek, Dominik Pfister, Sainitin Donakonda, Pamela Filpe, Annika Schneider, Melanie Laschinger, Daniel Hartmann, Norbert Hueser, Philippa Meiser, Felix Bayerl, Donato Inverso, Jennifer Wigger, Marcial Sebode, Rupert Oellinger, Roland Rad, Silke Hegenbarth, Martina Anton, Adrien Guillot, Andrew Bowman, Danijela HeideFlorian Mueller, Pierluigi Ramadori, Valentina Leone, Cristina Garcia-Caceres, Tim Gruber, Gabriel Seifert, Agnieszka M. Kabat, Jan-Philipp Malm, Simon Reider, Maria Effenberger, Susanne Roth, Adrian T. Billeter, Beat Mueller-Stich, Edward J. Pearce, Friedrich Koch-Nolte, Rafael Kaeser, Herbert Tilg, Robert Thimme, Tobias Boettler, Frank Tacke, Jean-Francois Dufour, Dirk Haller, Peter J. Murray, Ron Heeren, Dietmar Zehn, Jan P. Boettcher, Mathias Heikenwaelder, Percy A. Knolle^*

^*Corresponding author for this work

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Abstract

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer ^1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver ³, 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.

Original language	English
Pages (from-to)	444-449
Number of pages	31
Journal	Nature
Volume	592
Issue number	7854
DOIs	https://doi.org/10.1038/s41586-021-03233-8
Publication status	Published - 15 Apr 2021

Keywords

BIOLOGY
EFFECTOR FUNCTION
IL-15
INFLAMMATION
METABOLISM
MODELS
MOUSE
NONALCOHOLIC STEATOHEPATITIS
RELEASE
TRANSCRIPTION FACTORS
Transcription factors
Inflammation
Biology
Metabolism
Nonalcoholic steatohepatitis
Mouse
Il-15
Models
Effector function
Release

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10.1038/s41586-021-03233-8

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1 Erratum / corrigendum / retractions

Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH
Dudek, M., Pfister, D., Donakonda, S., Filpe, P., Schneider, A., Laschinger, M., Hartmann, D., Hüser, N., Meiser, P., Bayerl, F., Inverso, D., Wigger, J., Sebode, M., Öllinger, R., Rad, R., Hegenbarth, S., Anton, M., Guillot, A., Bowman, A., Heide, D., & 28 othersMüller, F., Ramadori, P., Leone, V., Garcia-Caceres, C., Gruber, T., Seifert, G., Kabat, A. M., Mallm, J-P., Reider, S., Effenberger, M., Roth, S., Billeter, A. T., Müller-Stich, B., Pearce, E. J., Koch-Nolte, F., Käser, R., Tilg, H., Thimme, R., Boettler, T., Tacke, F., Dufour, J-F., Haller, D., Murray, P. J., Heeren, R., Zehn, D., Böttcher, J. P., Heikenwälder, M. & Knolle, P. A., 27 May 2021, In: Nature. 593, 7860, p. E14-E14 1 p., E14.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

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Dudek, M., Pfister, D., Donakonda, S., Filpe, P., Schneider, A., Laschinger, M., Hartmann, D., Hueser, N., Meiser, P., Bayerl, F., Inverso, D., Wigger, J., Sebode, M., Oellinger, R., Rad, R., Hegenbarth, S., Anton, M., Guillot, A., Bowman, A., ... Knolle, P. A. (2021). Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH. Nature, 592(7854), 444-449. https://doi.org/10.1038/s41586-021-03233-8

@article{995851d88e194d3cafdc8b40030f1eb1,

title = "Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH",

abstract = "Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver 3, 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.",

keywords = "BIOLOGY, EFFECTOR FUNCTION, IL-15, INFLAMMATION, METABOLISM, MODELS, MOUSE, NONALCOHOLIC STEATOHEPATITIS, RELEASE, TRANSCRIPTION FACTORS, Transcription factors, Inflammation, Biology, Metabolism, Nonalcoholic steatohepatitis, Mouse, Il-15, Models, Effector function, Release",

author = "Michael Dudek and Dominik Pfister and Sainitin Donakonda and Pamela Filpe and Annika Schneider and Melanie Laschinger and Daniel Hartmann and Norbert Hueser and Philippa Meiser and Felix Bayerl and Donato Inverso and Jennifer Wigger and Marcial Sebode and Rupert Oellinger and Roland Rad and Silke Hegenbarth and Martina Anton and Adrien Guillot and Andrew Bowman and Danijela Heide and Florian Mueller and Pierluigi Ramadori and Valentina Leone and Cristina Garcia-Caceres and Tim Gruber and Gabriel Seifert and Kabat, {Agnieszka M.} and Jan-Philipp Malm and Simon Reider and Maria Effenberger and Susanne Roth and Billeter, {Adrian T.} and Beat Mueller-Stich and Pearce, {Edward J.} and Friedrich Koch-Nolte and Rafael Kaeser and Herbert Tilg and Robert Thimme and Tobias Boettler and Frank Tacke and Jean-Francois Dufour and Dirk Haller and Murray, {Peter J.} and Ron Heeren and Dietmar Zehn and Boettcher, {Jan P.} and Mathias Heikenwaelder and Knolle, {Percy A.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = apr,

day = "15",

doi = "10.1038/s41586-021-03233-8",

language = "English",

volume = "592",

pages = "444--449",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

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Dudek, M, Pfister, D, Donakonda, S, Filpe, P, Schneider, A, Laschinger, M, Hartmann, D, Hueser, N, Meiser, P, Bayerl, F, Inverso, D, Wigger, J, Sebode, M, Oellinger, R, Rad, R, Hegenbarth, S, Anton, M, Guillot, A, Bowman, A, Heide, D, Mueller, F, Ramadori, P, Leone, V, Garcia-Caceres, C, Gruber, T, Seifert, G, Kabat, AM, Malm, J-P, Reider, S, Effenberger, M, Roth, S, Billeter, AT, Mueller-Stich, B, Pearce, EJ, Koch-Nolte, F, Kaeser, R, Tilg, H, Thimme, R, Boettler, T, Tacke, F, Dufour, J-F, Haller, D, Murray, PJ, Heeren, R, Zehn, D, Boettcher, JP, Heikenwaelder, M & Knolle, PA 2021, 'Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH', Nature, vol. 592, no. 7854, pp. 444-449. https://doi.org/10.1038/s41586-021-03233-8

TY - JOUR

T1 - Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH

AU - Dudek, Michael

AU - Pfister, Dominik

AU - Donakonda, Sainitin

AU - Filpe, Pamela

AU - Schneider, Annika

AU - Laschinger, Melanie

AU - Hartmann, Daniel

AU - Hueser, Norbert

AU - Meiser, Philippa

AU - Bayerl, Felix

AU - Inverso, Donato

AU - Wigger, Jennifer

AU - Sebode, Marcial

AU - Oellinger, Rupert

AU - Rad, Roland

AU - Hegenbarth, Silke

AU - Anton, Martina

AU - Guillot, Adrien

AU - Bowman, Andrew

AU - Heide, Danijela

AU - Mueller, Florian

AU - Ramadori, Pierluigi

AU - Leone, Valentina

AU - Garcia-Caceres, Cristina

AU - Gruber, Tim

AU - Seifert, Gabriel

AU - Kabat, Agnieszka M.

AU - Malm, Jan-Philipp

AU - Reider, Simon

AU - Effenberger, Maria

AU - Roth, Susanne

AU - Billeter, Adrian T.

AU - Mueller-Stich, Beat

AU - Pearce, Edward J.

AU - Koch-Nolte, Friedrich

AU - Kaeser, Rafael

AU - Tilg, Herbert

AU - Thimme, Robert

AU - Boettler, Tobias

AU - Tacke, Frank

AU - Dufour, Jean-Francois

AU - Haller, Dirk

AU - Murray, Peter J.

AU - Heeren, Ron

AU - Zehn, Dietmar

AU - Boettcher, Jan P.

AU - Heikenwaelder, Mathias

AU - Knolle, Percy A.

PY - 2021/4/15

Y1 - 2021/4/15

N2 - Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver 3, 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.

AB - Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver 3, 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.

KW - BIOLOGY

KW - EFFECTOR FUNCTION

KW - IL-15

KW - INFLAMMATION

KW - METABOLISM

KW - MODELS

KW - MOUSE

KW - NONALCOHOLIC STEATOHEPATITIS

KW - RELEASE

KW - TRANSCRIPTION FACTORS

KW - Transcription factors

KW - Inflammation

KW - Biology

KW - Metabolism

KW - Nonalcoholic steatohepatitis

KW - Mouse

KW - Il-15

KW - Models

KW - Effector function

KW - Release

U2 - 10.1038/s41586-021-03233-8

DO - 10.1038/s41586-021-03233-8

M3 - Article

C2 - 33762736

SN - 0028-0836

VL - 592

SP - 444

EP - 449

JO - Nature

JF - Nature

IS - 7854

ER -

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

Abstract

Keywords

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Research output

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

Cite this