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CAR directs T cell adaptation to bile acids in the small intestine
Nature ( IF 42.778 ) Pub Date : 2021-04-07 , DOI: 10.1038/s41586-021-03421-6
Mei Lan Chen, Xiangsheng Huang, Hongtao Wang, Courtney Hegner, Yujin Liu, Jinsai Shang, Amber Eliason, Huitian Diao, HaJeung Park, Blake Frey, Guohui Wang, Sarah A. Mosure, Laura A. Solt, Douglas J. Kojetin, Alex Rodriguez-Palacios, Deborah A. Schady, Casey T. Weaver, Matthew E. Pipkin, David D. Moore, Mark S. Sundrud

Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1−/− or Rag2/ mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn’s disease and defines lymphocyte sub-specialization in the small intestine.



中文翻译:

CAR指导T细胞适应小肠中的胆汁酸

胆汁酸是在肝细胞中合成的脂质乳化代谢产物,通过肝脏和小肠1之间的肝肠循环在体内得以维持。作为清洁剂,胆汁酸会在肠肝组织2中引起毒性和炎症。核受体维持肝细胞和肠上皮细胞3中的胆汁酸稳态,但尚不清楚粘膜免疫细胞如何耐受小肠固有层(siLP)中的高浓度胆汁酸。CD4 + T效应(T eff)细胞上调siLP中异源生物转运蛋白MDR1(由Abcb1a编码)的表达,以预防胆汁酸中毒并抑制克罗恩氏病样小肠炎症4。在这里,我们确定了核异源生物受体CAR(由Nr1i3编码)作为T细胞中MDR1表达的调节剂,可以预防小鼠小肠的胆汁酸毒性和炎症。CAR的激活在浸入siLP但未浸入结肠的T eff细胞中诱导大规模转录重编程。CAR不仅像在肝细胞中一样在siLP T eff细胞中诱导解毒酶和转运蛋白的表达,而且还诱导关键的抗炎细胞因子IL-10的表达。因此,T细胞中的CAR缺乏加剧了T细胞重构的Rag1 -/-或 Rag2 - / -中的胆汁酸驱动性回肠炎。 小鼠,而CAR的药理学激活抑制了它。这些数据表明,CAR在渗透小肠的T细胞中发挥局部作用,以解毒胆汁酸并解决炎症。该程序的激活提供了一种治疗小肠克罗恩病的出人意料的策略,并定义了小肠中的淋巴细胞亚专业化。

更新日期:2021-04-08
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