Translational Research in Immunology and Inflammation, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.
Front Immunol. 2020 Jul 31;11:1711. doi: 10.3389/fimmu.2020.01711. eCollection 2020.
Non-alcoholic steatohepatitis (NASH) is a multisystem condition, involving the liver, adipose tissue, and immune system. Regulatory T (Treg) cells are a subset of T cells that exert an immune-controlling effect. Previously, a reduction of Treg cells in the visceral adipose tissue (VAT) was shown to be associated with a more severe degree of liver disease. We aimed to correct this immune disruption through adoptive cell transfer (ACT) of Treg cells. Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) for 20 weeks. Treg cells were isolated from the spleens of healthy 8 to 10-week-old C57BL/6J mice and were adoptively transferred to HFHFD-fed mice. PBS-injected mice served as controls. Plasma ALT and lipid levels were determined. Liver and adipose tissue were assessed histologically. Cytotoxic T (Tc), Treg, T helper (Th) 1 and Th17 cells were characterized in VAT, liver, subcutaneous adipose tissue (SAT), blood, and spleen via flow cytometry. Gene expression analysis was performed in SAT and VAT of mice fed either the HFHFD or a control diet for 10-32 weeks. ACT increased Treg cells in SAT, but not in any of the other tissues. Moreover, the ACT induced a decrease in Th1 cells in SAT, liver, blood, and spleen. Higher plasma ALT levels and a higher degree of steatosis were observed in ACT mice, whereas the other HFHFD-induced metabolic and histologic disruptions were unaffected. Expression analysis of genes related to Treg-cell proliferation revealed a HFHFD-induced decrease in all investigated genes in the SAT, while in the VAT the expression of these genes was largely unaffected, except for a decrease in . ACT of Treg cells in HFHFD-fed mice exacerbated hepatic steatosis, which was possibly related to the increase of Treg cells in the SAT and/or the general decrease in Th1 cells. Moreover, the HFHFD-induced decrease in expression appeared critical in the decrease of Treg cells at the level of the VAT and the inability to replenish the amount of Treg cells by the ACT, while the mechanism of Treg cell accumulation at the level of the SAT remained unclear.
非酒精性脂肪性肝炎（NASH）是一种多系统疾病，涉及肝脏、脂肪组织和免疫系统。调节性 T（Treg）细胞是 T 细胞的一个亚群，具有免疫控制作用。先前的研究表明，内脏脂肪组织（VAT）中 Treg 细胞的减少与更严重的肝病程度有关。我们旨在通过 Treg 细胞的过继细胞转移（ACT）来纠正这种免疫紊乱。雄性 8 周龄 C57BL/6J 小鼠用高脂肪高果糖饮食（HFHFD）喂养 20 周。从健康 8 至 10 周龄 C57BL/6J 小鼠的脾脏中分离出 Treg 细胞，并过继转移到 HFHFD 喂养的小鼠中。注射 PBS 的小鼠作为对照。测定血浆 ALT 和脂质水平。通过组织学评估肝和脂肪组织。通过流式细胞术在 VAT、肝脏、皮下脂肪组织（SAT）、血液和脾脏中对细胞毒性 T（Tc）、Treg、辅助性 T（Th）1 和 Th17 细胞进行了特征描述。对用 HFHFD 或对照饮食喂养 10-32 周的小鼠的 SAT 和 VAT 进行基因表达分析。ACT 增加了 SAT 中的 Treg 细胞，但不增加任何其他组织中的 Treg 细胞。此外，ACT 诱导 SAT、肝脏、血液和脾脏中 Th1 细胞减少。ACT 小鼠的血浆 ALT 水平升高，脂肪变性程度更高，而其他 HFHFD 诱导的代谢和组织学紊乱不受影响。与 Treg 细胞增殖相关的基因表达分析显示，HFHFD 诱导 SAT 中所有研究基因表达降低，而 VAT 中这些基因的表达基本不受影响，除了 表达降低。HFHFD 喂养的小鼠的 Treg 细胞 ACT 加剧了肝脂肪变性，这可能与 SAT 中 Treg 细胞的增加和/或 Th1 细胞的普遍减少有关。此外，HFHFD 诱导的 表达降低在 VAT 中 Treg 细胞数量减少和 ACT 无法补充 Treg 细胞数量方面似乎是关键的，而 SAT 中 Treg 细胞积累的机制仍不清楚。
