CXCR3+ CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury
CXCR3+ CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury
复制标题
DOI：
10.4049/jimmunol.176.10.6313
复制
发表时间：
2006-05-15
影响因子：
4.4
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Zhai, Yuan;Shen, Xiu-da;Kupiec-Weglinski, Jerzy W.
缺血再灌注损伤（IRI）是一种先天性免疫主导的炎症反应，在缺乏外源性Ag的情况下发生。最近强调的T细胞在IRI中的作用提出了一个问题，即T淋巴细胞如何与先天免疫系统相互作用并在没有Ag刺激的情况下发挥作用。本研究探讨了先天免疫诱导的大鼠同基因原位肝移植（奥尔特）中T细胞募集和激活的机制。在VC中于威斯康星州大学溶液中冷藏（24-36 h）后诱导肝脏IRI。在移植后4小时通过cDNA微阵列鉴定有助于IRI的基因产物。IRI触发CXCL 10、沿着CXCL 9和11的肝内表达增加。CXCR 3配体诱导的重要性通过中和抗CXCR 3 Ab治疗改善肝细胞损伤和提高30小时冷储存OLT的14天存活率的能力来证明（对照组为95% vs 40%; p < 0.01）。免疫组织学分析证实治疗后OLT中CXCR 3（+）和CD 4（+）T细胞浸润减少。有趣的是，抗CXCR 3 Ab没有抑制肝脏中的先天性免疫激活，如IL-1 β、IL-6、诱导型NO合酶和多种中性粒细胞/单核因子靶向趋化因子程序的水平增加所证明的。总之，本研究证明了在没有外源性Ag刺激的情况下T细胞募集和功能的新机制。通过记录先天免疫功能的执行需要CXCR 3（+）CD 4（+）T细胞，它突出了CXCR 3趋化因子生物学在肝脏IRI的病理生理学中对于先天免疫到适应性免疫的连续体的关键作用。
Ischemia-reperfusion injury (IRI), an innate immune-dominated inflammatory response, develops in the absence of exogenous Ags. The recently highlighted role of T cells in IRI raises a question as to how T lymphocytes interact with the innate immune system and function with no Ag stimulation. This study dissected the mechanism of innate immune-induced T cell recruitment and activation in rat syngeneic orthotopic liver transplantation (OLT) model. Liver IRI was induced after cold storage (24-36 h) at VC in University of Wisconsin solution. Gene products contributing to IRI were identified by cDNA microarray at 4-h post-transplant. IRI triggered increased intrahepatic expression of CXCL10, along with CXCL9 and 11. The significance of CXCR3 ligand induction was documented by the ability of neutralizing anti-CXCR3 Ab treatment to ameliorate hepatocellular damage and improve 14-day survival of 30-h cold-stored OLTs (95 vs 40% in controls; p < 0.01). Immunohistology analysis confirmed reduced CXCR3(+) and CD4(+) T cell infiltration in OLTs after treatment. Interestingly, anti-CXCR3 Ab did not suppress innate immune activation in the liver, as evidenced by increased levels of IL-1 beta, IL-6, inducible NO synthase, and multiple neutrophil/monokine-targeted chemokine programs. In conclusion, this study demonstrates a novel mechanism of T cell recruitment and function in the absence of exogenous Ag stimulation. By documenting that the execution of innate immune function requires CXCR3(+)CD4(+) T cells, it highlights the critical role of CXCR3 chemokine biology for the continuum of innate to adaptive immunity in the pathophysiology of liver IRI.