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

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Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. / Dudek, Michael; Pfister, Dominik; Donakonda, Sainitin; Filpe, Pamela; Schneider, Annika; Laschinger, Melanie; Hartmann, Daniel; Meiser, Philippa; Bayerl, Felix; Inverso, Donato; Wigger, Jennifer; Sebode, Marcial; Öllinger, Rupert; Rad, Roland; Hegenbarth, Silke; Anton, Martina; Guillot, Adrien; Bowman, Andrew; Heide, Danijela; Müller, Florian; Ramadori, Pierluigi; Leone, Valentina; Garcia-Caceres, Cristina; Gruber, Tim; Seifert, Gabriel; Kabat, Agnieszka M; Malm, Jan-Philipp; Reider, Simon; Effenberger, Maria; Roth, Susanne; Billeter, Adrian T; Müller-Stich, Beat; Pearce, Edward J; Koch-Nolte, Friedrich; Käser, Rafael; Tilg, Herbert; Thimme, Robert; Böttler, Tobias; Tacke, Frank; Dufour, Jean-Francois; Haller, Dirk; Murray, Peter J; Heeren, Ron; Zehn, Dietmar; Böttcher, Jan P; Heikenwälder, Mathias; Knolle, Percy A.

In: NATURE, Vol. 592, No. 7854, 04.2021, p. 444-449.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Dudek, M, Pfister, D, Donakonda, S, Filpe, P, Schneider, A, Laschinger, M, Hartmann, D, Meiser, P, Bayerl, F, Inverso, D, Wigger, J, Sebode, M, Öllinger, R, Rad, R, Hegenbarth, S, Anton, M, Guillot, A, Bowman, A, Heide, D, Müller, 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, Müller-Stich, B, Pearce, EJ, Koch-Nolte, F, Käser, R, Tilg, H, Thimme, R, Böttler, T, Tacke, F, Dufour, J-F, Haller, D, Murray, PJ, Heeren, R, Zehn, D, Böttcher, JP, Heikenwälder, 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

APA

Dudek, M., Pfister, D., Donakonda, S., Filpe, P., Schneider, A., Laschinger, M., Hartmann, D., Meiser, P., Bayerl, F., Inverso, D., Wigger, J., Sebode, M., Öllinger, R., Rad, R., Hegenbarth, S., Anton, M., Guillot, A., Bowman, A., Heide, D., ... 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

Vancouver

Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. NATURE. 2021 Apr;592(7854):444-449. https://doi.org/10.1038/s41586-021-03233-8

Bibtex

@article{d4e2b26156bb45dab21fdc3857707612,
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 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.",
author = "Michael Dudek and Dominik Pfister and Sainitin Donakonda and Pamela Filpe and Annika Schneider and Melanie Laschinger and Daniel Hartmann and Philippa Meiser and Felix Bayerl and Donato Inverso and Jennifer Wigger and Marcial Sebode and Rupert {\"O}llinger and Roland Rad and Silke Hegenbarth and Martina Anton and Adrien Guillot and Andrew Bowman and Danijela Heide and Florian M{\"u}ller 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 M{\"u}ller-Stich and Pearce, {Edward J} and Friedrich Koch-Nolte and Rafael K{\"a}ser and Herbert Tilg and Robert Thimme and Tobias B{\"o}ttler and Frank Tacke and Jean-Francois Dufour and Dirk Haller and Murray, {Peter J} and Ron Heeren and Dietmar Zehn and B{\"o}ttcher, {Jan P} and Mathias Heikenw{\"a}lder and Knolle, {Percy A}",
year = "2021",
month = apr,
doi = "10.1038/s41586-021-03233-8",
language = "English",
volume = "592",
pages = "444--449",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7854",

}

RIS

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 - Meiser, Philippa

AU - Bayerl, Felix

AU - Inverso, Donato

AU - Wigger, Jennifer

AU - Sebode, Marcial

AU - Öllinger, Rupert

AU - Rad, Roland

AU - Hegenbarth, Silke

AU - Anton, Martina

AU - Guillot, Adrien

AU - Bowman, Andrew

AU - Heide, Danijela

AU - Müller, 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 - Müller-Stich, Beat

AU - Pearce, Edward J

AU - Koch-Nolte, Friedrich

AU - Käser, Rafael

AU - Tilg, Herbert

AU - Thimme, Robert

AU - Böttler, Tobias

AU - Tacke, Frank

AU - Dufour, Jean-Francois

AU - Haller, Dirk

AU - Murray, Peter J

AU - Heeren, Ron

AU - Zehn, Dietmar

AU - Böttcher, Jan P

AU - Heikenwälder, Mathias

AU - Knolle, Percy A

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-021-03233-8

DO - 10.1038/s41586-021-03233-8

M3 - SCORING: Journal article

C2 - 33762736

VL - 592

SP - 444

EP - 449

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7854

ER -