Warren Alessandra, Le Couteur David G, Fraser Robin, Bowen David G, McCaughan Geoffrey W, Bertolino Patrick
Centre for Education and Research on Ageing (CERA) and the ANZAC Research Institute, Concord RG Hospital and University of Sydney, Sydney, Australia.
Hepatology. 2006 Nov;44(5):1182-90. doi: 10.1002/hep.21378.
The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node-activated T cells, liver-activated T cells are short-lived, a mechanism that might contribute to the "liver tolerance effect." Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8(+) T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that naïve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating naïve CD8(+) T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion, this study has identified, at the ultrastructural level, a unique type of interaction between naïve T lymphocytes and liver parenchymal cells in vivo. These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.
肝脏具有诱导免疫耐受的既定能力。最近的证据表明，这种独特的特性可能与其独特的结构有关，该结构允许T细胞在不依赖淋巴组织的情况下在原位被激活。与淋巴结激活的T细胞不同，肝脏激活的T细胞寿命较短，这一机制可能有助于产生“肝脏耐受效应”。尽管已经证明了肝细胞作为致耐受性抗原呈递细胞的潜在作用，但在生理环境中这些细胞是否能够与CD8(+) T细胞相互作用的问题仍存在争议。与免疫教条相悖的是，传统观点认为幼稚T淋巴细胞会被不可穿透的内皮屏障阻止与非淋巴器官内的实质细胞相互作用，但我们在此表明，肝窦内皮细胞（LSEC）的独特形态允许淋巴细胞与肝细胞之间发生相互作用。通过电子显微镜，我们证明肝脏驻留淋巴细胞以及循环幼稚CD8(+) T细胞通过穿透LSEC的内皮窗孔的细胞质延伸与肝细胞直接接触。此外，初级T细胞激活所需分子MHC I类分子和细胞间黏附分子-1（ICAM-1）在肝细胞上极化至窦周细胞膜，从而最大限度地增加了与循环淋巴细胞相互作用的机会。总之，本研究在超微结构水平上确定了幼稚T淋巴细胞与肝脏实质细胞在体内的一种独特相互作用类型。这些结果对病毒性肝炎的发病机制具有启示意义，其中肝细胞可能是主要的抗原呈递细胞，并且对淋巴细胞通过肝脏时免疫耐受的发展也具有启示意义。
