Biliary obstruction results in PD-1-dependent liver T cell dysfunction and acute inflammation mediated by Th17 cells and neutrophils
Biliary obstruction results in PD-1-dependent liver T cell dysfunction and acute inflammation mediated by Th17 cells and neutrophils
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DOI：
10.1189/jlb.0313137
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发表时间：
2013-10-01
影响因子：
5.5
通讯作者：
Katz, Steven C.
中科院分区：
文献类型：
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作者：
Licata, Lauren A.;Nguyen, Cang T.;Katz, Steven C.
胆道梗阻是一种常见的临床问题，与肝内炎症和免疫功能受损有关。众所周知，PD-1介导T细胞功能障碍，但据报道，在各种损伤模型中，PD-1可促进和减轻急性炎症。通过建立小鼠BDL模型，我们研究了肝内PD-1表达对LTC功能、炎症和胆汁淤积的影响。BDL后，LTCs中PD-1表达显著升高。BDL后PD-1表达增加与LTC增殖减少和ifn - γ产生减少有关。消除PD-1的表达导致BDL后LTC的增殖能力显著提高，此外还有更多的免疫刺激细胞因子谱。PD-1（-/-）小鼠不仅LTC功能恢复，而且与BDL后的WT动物相比，胆道细胞损伤、胆汁淤积和炎症程度也明显减轻。pd -1介导的BDL后急性炎症与肝内中性粒细胞和Th17细胞群的扩增有关，后者依赖于IL-6。PD-1阻断是一种有吸引力的策略，可以逆转肝内免疫抑制，同时限制炎症性肝损伤。
Biliary obstruction is a common clinical problem that is associated with intrahepatic inflammation and impaired immunity. PD-1 is well known to mediate T cell dysfunction but has been reported to promote and attenuate acute inflammation in various injury models. With the use of a well-established murine model of BDL, we studied the effects of intrahepatic PD-1 expression on LTC function, inflammation, and cholestasis. Following BDL, PD-1 expression increased significantly among LTCs. Increased PD-1 expression following BDL was associated with decreased LTC proliferation and less IFN-gamma production. Elimination of PD-1 expression resulted in significantly improved proliferative capacity among LTC following BDL, in addition to a more immunostimulatory cytokine profile. Not only was LTC function rescued in PD-1(-/-) mice, but also, the degrees of biliary cell injury, cholestasis, and inflammation were diminished significantly compared with WT animals following BDL. PD-1-mediated acute inflammation following BDL was associated with expansions of intrahepatic neutrophil and Th17 cell populations, with the latter dependent on IL-6. PD-1 blockade represents an attractive strategy for reversing intrahepatic immunosuppression while limiting inflammatory liver damage.