The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity
The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity
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DOI：
10.1172/jci200421593
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发表时间：
2004-09-01
影响因子：
15.9
通讯作者：
Bertolino, P
中科院分区：
文献类型：
--
作者：
Bowen, DG;Zen, M;Bertolino, P
肝脏免疫生物学是矛盾的：尽管肝脏具有不同寻常的耐受性，但它也是对抗多种病原体的有效免疫反应的部位，并受到免疫介导的病理的影响。这种二分法背后的机制尚不清楚。在先前的研究表明肝脏可能作为原代T细胞激活的位点之后，我们在这里证明了肝脏中免疫和耐受性之间的平衡是通过肝脏和次级淋巴组织之间对CD8(+) T细胞的原代激活的竞争来建立的，免疫结果由初始激活位点决定。利用抗原在肝脏和淋巴结内均表达的转基因小鼠模型，我们发现在淋巴结内激活的初始CD8(+) T细胞能够介导肝炎，而在肝脏内进行初级激活的细胞表现出缺陷的细胞毒性功能和缩短的半衰期，并且不介导肝细胞损伤。这些新发现的意义可能不仅与外周耐受性的正常维持有关，而且与肝异体移植耐受性和慢性病毒性肝炎的免疫发病机制有关。
Hepatic immunobiology is paradoxical: although the liver possesses unusual tolerogenic properties, it is also the site of effective immune responses against multiple pathogens and subject to immune-mediated pathology. The mechanisms underlying this dichotomy remain unclear. Following previous work demonstrating that the liver may act as a site of primary T cell activation, we demonstrate here that the balance between immunity and tolerance in this organ is established by competition for primary activation of CD8(+) T cells between the liver and secondary lymphoid tissues, with the immune outcome determined by the initial site of activation. Using a transgenic mouse model in which antigen is expressed within both liver and lymph nodes, we show that while naive CD8(+) T cells activated within the lymph nodes were capable of mediating hepatitis, cells undergoing primary activation within the liver exhibited defective cytotoxic function and shortened half-life and did not mediate hepatocellular injury. The implications of these novel findings may pertain not only to the normal maintenance of peripheral tolerance, but also to hepatic allograft tolerance and the immunopathogenesis of chronic viral hepatitis.