Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH
| العنوان: | Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH |
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| المؤلفون: | Pamela Filpe, Melanie Laschinger, Cristina García-Cáceres, Silke Hegenbarth, Dominik Pfister, Adrien Guillot, Valentina Leone, Simon Reider, Dietmar Zehn, Pierluigi Ramadori, Robert Thimme, Roland Rad, Gabriel Seifert, Mathias Heikenwalder, Martina Anton, Danijela Heide, Marcial Sebode, Tim Gruber, Daniel Hartmann, Jennifer Wigger, Susanne Roth, Rafael Käser, Donato Inverso, Friedrich Koch-Nolte, Michael Dudek, Jan P. Böttcher, Annika Schneider, Philippa Meiser, Sainitin Donakonda, Frank Tacke, Dirk Haller, Adrian T. Billeter, Jean-François Dufour, Edward J. Pearce, Felix Bayerl, Ron M. A. Heeren, Beat P. Müller-Stich, Florian Müller, Maria Effenberger, Peter J. Murray, Andrew P. Bowman, Agnieszka M. Kabat, Jan-Philipp Mallm, Herbert Tilg, Rupert Öllinger, Norbert Hüser, Percy A. Knolle, Tobias Boettler |
| المساهمون: | Imaging Mass Spectrometry (IMS), RS: M4I - Imaging Mass Spectrometry (IMS) |
| المصدر: | Nature Nature, 592(7854), 444-449. Nature Publishing Group Nature 592, 444-449 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Mouse, MODELS, BIOLOGY, EFFECTOR FUNCTION, FOXO1, Inflammation, METABOLISM, digestive system, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Immune system, Downregulation and upregulation, medicine, Cytotoxic T cell, 610 Medicine & health, RELEASE, Il-15, Multidisciplinary, biology, NONALCOHOLIC STEATOHEPATITIS, Purinergic receptor, nutritional and metabolic diseases, medicine.disease, digestive system diseases, TRANSCRIPTION FACTORS, 030104 developmental biology, Granzyme, 030220 oncology & carcinogenesis, Cancer research, biology.protein, medicine.symptom |
| الوصف: | Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps . 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-021-03233-8 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c275477f29e6dfacf1c754a2fedea334 https://doi.org/10.1038/s41586-021-03233-8 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c275477f29e6dfacf1c754a2fedea334 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14764687 00280836 |
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| DOI: | 10.1038/s41586-021-03233-8 |