Ajuebor Maureen N, Aspinall Alex I, Zhou Feng, Le Tai, Yang Yang, Urbanski Stefan J, Sidobre Stéphané, Kronenberg Mitchell, Hogaboam Cory M, Swain Mark G
Gastrointestinal Research Group, Diabetes and Endocrine Research Group, and Department of Histopathology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
J Immunol. 2005 Jun 15;174(12):8027-37. doi: 10.4049/jimmunol.174.12.8027.
Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-gamma, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.
暴发性肝衰竭（FLF）由一系列事件组成，始于假定的免疫系统全身性失控激活。FLF的病因仍不明确。在本研究中，我们证明CCR5缺陷通过防止活化的肝脏CD1d限制性自然杀伤T细胞（而非传统T细胞）因活化诱导的凋亡而死亡，从而促进小鼠在注射刀豆蛋白A后急性FLF的发展。CCR5缺陷的自然杀伤T细胞在注射刀豆蛋白A后对活化诱导的凋亡具有抗性，并非由于Fas驱动的死亡途径存在缺陷。此外，CCR5缺陷小鼠的FLF也与肝脏中CCR5缺陷的自然杀伤T细胞有关，相对于野生型自然杀伤T细胞，这些细胞产生更多的IL-4，但不产生IFN-γ。此外，用IL-4单克隆抗体或NK1.1单克隆抗体治疗可消除这些小鼠的FLF。我们提出，CCR5缺陷可能通过防止肝脏自然杀伤T细胞凋亡和调节自然杀伤T细胞功能，使个体易患FLF，从而确立了CCR5在这种灾难性肝脏疾病发展中的新作用，该作用独立于白细胞募集。
