Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH
Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH
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DOI：
10.1038/s41586-021-03233-8
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发表时间：
2021-03-24
期刊：
影响因子：
64.8
通讯作者：
Knolle, Percy A.
中科院分区：
文献类型：
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作者：
Dudek, Michael;Pfister, Dominik;Knolle, Percy A.
在非酒精性脂肪性肝炎的小鼠模型中，肝脏驻留的CD 8 T细胞在免疫病理学中具有重要作用，其通过在顺序的转录和代谢活化步骤之后变得具有自身攻击性。非酒精性脂肪性肝炎（NASH）是与肥胖相关的全身性代谢疾病的表现，并且引起肝脏疾病和癌症（1，2）。代谢物的积累导致肝脏中的细胞应激和炎症（3），但对NASH中肝损伤的机制理解尚不完整。在这里，使用显示人类NASH关键特征的临床前小鼠模型（以下称为NASH小鼠），我们发现T细胞在肝脏免疫病理学中不可或缺的作用。我们检测了CD 8 T细胞的肝脏积累，其表型结合了组织驻留（CXCR 6）与效应子（颗粒酶）和耗竭（PD 1）特征。肝脏CXCR 6（+）CD 8 T细胞的特征在于FOXO 1转录因子的低活性，并且在NASH小鼠和NASH患者中丰富。从机制上讲，IL-15诱导FOXO 1下调和CXCR 6上调，这共同使肝脏驻留的CXCR 6（+）CD 8 T细胞对代谢刺激（包括乙酸盐和细胞外ATP）敏感，并共同引发自身攻击。来自NASH小鼠或NASH患者肝脏的CXCR 6（+）CD 8 T细胞具有相似的转录特征，并在通过P2 X7嘌呤能受体发出信号后以MHC I类非依赖性方式显示出细胞的自身攻击性杀伤。这种通过自身攻击性CD 8 T细胞的杀伤从根本上不同于通过抗原特异性细胞的杀伤，抗原特异性细胞在机制上区分了自身攻击性和保护性T细胞免疫。
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.