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PNAS:揭示病毒促使肝脏防御机制衰弱的分子机制

来源:生物谷 2014-06-20 09:34

2014年6月20日 讯 /生物谷BIOON/ --肝脏是机体中可以修改免疫反应的唯一器官,但是其又为强烈的免疫攻击提供了缺口,近日,来自悉尼大学的研究人员通过研究揭示了发生这一原因的分子机制,相关研究成果刊登于国际杂志PNAS上。相关研究为开发改善慢性肝炎的疗法提供了一定思路。

揭开这一谜题的关键是肝脏中免疫系统的T细胞,研究人员发现,当肝脏中的T细胞“遇到”一系列可以产生异体蛋白的细胞时,其就会以正常途径发挥功能,即刺激细胞的产生来遏制这种异体蛋白的产生;但当肝脏中的T细胞“遇到”大量异体蛋白质时(异体蛋白的水平超过一定阈值),T细胞就会失去功能,这种防御系统的削弱就是肝脏的致命弱点,从而使得肝脏对病毒的复制变得易感。

文章中,研究者Patrick Bertolino教授表示,肝炎病毒的复制非常快,其可以迅速扩散至肝脏细胞中,产生许多异体蛋白质来抑制肝脏T细胞的免疫效应;而在感染初期这个过程往往会很缓慢,因此研究者认为在感染初期肝脏的免疫系统可以很有效地对病毒进行清除。

研究者表示,下一步他们将通过研究来确定由高浓度病毒蛋白引发的T细胞功能衰退,是否可以通过某些途径来恢复;目前研究人员已经在小鼠机体中进行研究揭示了小鼠机体受损的T细胞可以恢复功能。本文研究为开发新型抵御肝炎病毒感染的疗法提供了一定的思路和线索。(生物谷Bioon.com)

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Szun Szun Taya,b, Yik Chun Wonga, David M. McDonalda, Nicole A. W. Wooda, Ben Roedigerb, Frederic Sierroa, Claire Mcguffoga, Ian E. Alexanderc, G. Alex Bishopd, Jennifer R. Gamblee, Wolfgang Weningerb,f, Geoffrey W. McCaughana, Patrick Bertolinoa,1,2, and David G. Bowena,d,1,2

CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions.

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