Institute for Molecular Engineering, University of Chicago, Chicago, IL, United States.
Institute for Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Front Immunol. 2021 Mar 3;12:555095. doi: 10.3389/fimmu.2021.555095. eCollection 2021.
Hepatocytes compose up to 80% of the total liver and have been indicated as important players in the induction of immunologic tolerance in this organ. We show that hepatocytes possess the molecular machinery required for the cross-presentation of extracellular antigens. Using a derivative of the model antigen ovalbumin (OVA) covalently modified with a polymer containing multiple N-acetylgalactosamine residues (pGal-OVA) that enhance extracellular antigen uptake by mimicking the glycome of apoptotic debris, we show efficient hepatocyte-dependent induction of cross-tolerance of both adoptively transferred OT-I cells and endogenous OVA-specific CD8 T lymphocytes, for example inducing tolerance to OVA-expressing skin transplants. Our study confirms that hepatocytes are capable of inducing peripheral tolerogenesis and provides proof of concept that they may be a valuable candidate for targeted tolerogenic treatments.
肝细胞占肝脏总重量的 80%，被认为是诱导器官免疫耐受的重要因素。我们发现，肝细胞具有对外源抗原进行交叉呈递所需的分子机制。我们使用模型抗原卵清蛋白（OVA）的衍生物，该衍生物与含有多个 N-乙酰半乳糖胺残基的聚合物共价结合（pGal-OVA），通过模拟细胞凋亡碎片的聚糖结构来增强细胞外抗原摄取，我们发现这种方法可以有效地诱导通过过继转移的 OT-I 细胞和内源性 OVA 特异性 CD8 T 淋巴细胞的交叉耐受，例如诱导对表达 OVA 的皮肤移植物的耐受。我们的研究证实了肝细胞能够诱导外周耐受发生，并为其可能成为有针对性的免疫耐受治疗的有价值的候选者提供了概念验证。
