小柯机器人

德国慕尼黑工业大学Percy A. Knolle小组发现，自身攻击性CXCR6⁺CD8 T细胞可引起NASH的肝免疫病理。相关论文于2021年3月24日在线发表在《自然》杂志上。

通过使用表现出人类非酒精性脂肪性肝炎（NASH）关键特征的临床前小鼠模型（以下称NASH小鼠），研究人员发现T细胞在肝免疫病理学中起着不可或缺的作用。研究人员检测到CD8 T细胞的肝蓄积，其表型将组织驻留（CXCR6）与效应子（颗粒酶）和精疲力竭（PD1）的特征相结合。肝CXCR6⁺CD8 T细胞的特征在于FOXO1转录因子的活性低，并且在NASH小鼠和NASH患者中富集。

从机理上讲，IL-15诱导FOXO1下调和CXCR6上调，共同使肝脏驻留的CXCR6⁺CD8 T细胞易受代谢刺激（包括乙酸盐和细胞外ATP），并共同触发自身攻击。来自NASH小鼠或NASH患者肝脏的CXCR6⁺CD8 T细胞具有相似的转录特征，并在通过P2X7嘌呤能受体发出信号后以不依赖MHC-I的方式表现出对细胞的自身攻击性杀伤。自身攻击性CD8 T细胞的杀伤与抗原特异性细胞的杀伤从根本上不同，后者从机制上区分了自身攻击性T细胞和保护性T细胞免疫。

据介绍，NASH是与肥胖有关的全身性代谢疾病的一种表现，会引起肝脏疾病和癌症。代谢物的积累会导致肝脏中的细胞应激和炎症，但是对NASH中肝损伤的机理了解尚不完善。

附：英文原文

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

Author: Michael Dudek, Dominik Pfister, Sainitin Donakonda, Pamela Filpe, Annika Schneider, Melanie Laschinger, Daniel Hartmann, Norbert Hser, Philippa Meiser, Felix Bayerl, Donato Inverso, Jennifer Wigger, Marcial Sebode, Rupert llinger, Roland Rad, Silke Hegenbarth, Martina Anton, Adrien Guillot, Andrew Bowman, Danijela Heide, Florian Mller, 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 Mller-Stich, Edward J. Pearce, Friedrich Koch-Nolte, Rafael Kser, Herbert Tilg, Robert Thimme, Tobias Bttler, Frank Tacke, Jean-Francois Dufour, Dirk Haller, Peter J. Murray, Ron Heeren, Dietmar Zehn, Jan P. Bttcher, Mathias Heikenwlder, Percy A. Knolle

Issue&Volume: 2021-03-24

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.

DOI: 10.1038/s41586-021-03233-8

Source: https://www.nature.com/articles/s41586-021-03233-8

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