Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, North Carolina.
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Am J Physiol Gastrointest Liver Physiol. 2020 Feb 1;318(2):G211-G224. doi: 10.1152/ajpgi.00040.2019. Epub 2019 Nov 11.
Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8 T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8 T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8 T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8 T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8 T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8 T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8 T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8 T cells may be a novel approach for treatment of obesity-associated NASH. Our study demonstrates that CD8 T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8 T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8 T cells are key players in obesity-associated NASH.
非酒精性脂肪性肝炎（NASH）在西方国家由于肥胖症的流行而有所增加。目前的研究兴趣集中在鉴定浸润肝脏的免疫细胞的类型和功能，以及介导其在 NASH 中募集和激活的关键因素。我们研究了肥胖和非肥胖 NASH 条件下 CD8 T 细胞的功能和表型。我们发现，肥胖 NASH 伴肝硬化患者肝脏中 CD8 染色升高，与肝星状细胞（HSC）激活的标志物α-平滑肌肌动蛋白呈正相关。与肥胖性肝脂肪变性小鼠相比，肥胖和高脂血症 NASH 小鼠肝脏中 CD8 T 细胞升高了 3.5 倍。从这些小鼠分离的肝脏 CD8 T 细胞表达细胞毒性的 IL-10 表达表型，并且 CD8 T 细胞耗竭导致肝炎症、HSC 激活和巨噬细胞积聚显著减少。此外，肥胖和高脂血症 NASH 小鼠的肝 CD8 T 细胞在体外和体内激活 HSCs。有趣的是，在瘦 NASH 小鼠模型中，CD8 T 细胞的耗竭和敲低并不影响肝炎症或 HSC 激活。我们证明，在肥胖/高脂血症条件下，CD8 T 细胞是 NASH 进展的关键调节因子，而在非肥胖条件下，它们在驱动疾病方面的作用最小。因此，针对 CD8 T 细胞的治疗方法可能是治疗肥胖相关 NASH 的一种新方法。我们的研究表明，CD8 T 细胞是主要的肝 T 细胞群体，在肥胖型 NASH 模型中升高，并直接激活肝星状细胞。相比之下，我们发现瘦 NASH 模型中的 CD8 T 细胞不会调节与 NASH 相关的炎症或星状细胞激活。因此，据我们所知，我们首次证明肝 CD8 T 细胞是肥胖相关 NASH 的关键参与者。
