Differential priming of CD8 and CD4 T-Cells in animal models of autoimmune hepatitis and cholangitis
Differential priming of CD8 and CD4 T-Cells in animal models of autoimmune hepatitis and cholangitis
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DOI：
10.1002/hep.21796
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发表时间：
2007-10-01
期刊：
影响因子：
13.5
通讯作者：
Schott, Eckart
中科院分区：
文献类型：
--
作者：
Derkow, Katja;Loddenkemper, Christoph;Schott, Eckart
自身免疫性肝病的发病机制知之甚少。动物模型是必要的，以研究抗原呈递和启动的T细胞的背景下，在肝脏中的自身免疫。产生转基因小鼠模型，其中模型抗原卵清蛋白在肝细胞（TF-0 VA）或胆管细胞（ASBT-0 VA）中表达。将特异于卵清蛋白的转基因OT-I（CD 8）或OT-II（CD 4）T细胞过继转移到TF-0 VA和ASBTOVA小鼠中以诱导抗原特异性T细胞的体内引发。研究了T细胞迁移和活化以及肝脏炎症的诱导。OT-I T细胞优先位于两种小鼠品系的肝脏，而没有观察到OT-II T细胞向肝脏的迁移。OT-I T细胞在TF-0 VA小鼠的肝脏和ASBT-0 VA小鼠的肝脏和肝脏引流淋巴结中增殖。OT-II CD 4 T细胞在TF-0 VA小鼠的脾和肝引流淋巴结中活化，但在ASBT-0 VA小鼠中未活化。OT-I T细胞的转移导致ASBT-OVA和TF-OVA小鼠肝脏中组织学上不同的炎性病症，并引起肝损伤，如通过血清丙氨酸氨基转移酶升高所确定的。结论：在肝细胞中表达的抗原被呈递给CD 8和CD 4 T细胞，而在胆管细胞中表达的相同抗原被呈递给CD 8 T细胞而不是CD 4 T细胞。在这两种模型中，CD 8 T细胞的激活发生在肝脏内并导致肝脏炎症。本文所建立的模型对研究肝脏中T细胞的启动及其在肝脏自身免疫性疾病发展中的作用具有重要价值。
The pathogenesis of autoimmune liver diseases is poorly understood. Animal models are necessary to investigate antigen presentation and priming of T-cells in the context of autoimmunity in the liver. Transgenic mouse models were generated in which the model antigen ovalbumin is expressed in hepatocytes (TF-OVA) or cholangiocytes (ASBT-OVA). Transgenic OT-I (CD8) or OT-II (CD4) T-cells specific for ovalbumin were adoptively transferred into TF-OVA and ASBTOVA mice to induce in vivo priming of antigen-specific T-cells. T-cell migration and activation, as well as induction of liver inflammation, were studied. OT-I T-cells preferentially located to the liver of both mouse strains whereas no migration of OT-II T-cells to the liver was observed. OT-I T-cells proliferated in the liver of TF-OVA mice and the liver and liver draining lymph nodes of ASBT-OVA mice. OT-II CD4 T-cells were activated in spleen and liver draining lymph node of TF-OVA mice but not in ASBT-OVA mice. Transfer of OT-I T-cells led to histologically distinct inflammatory conditions in the liver of ASBT-OVA and TF-OVA mice and caused liver injury as determined by the elevation of serum alanine aminotransferase. Conclusion: An antigen expressed in hepatocytes is presented to CD8 and CD4 T-cells, whereas the same antigen expressed in cholangiocytes is presented to CD8 but not CD4 T-cells. In both models, activation of CD8 T-cells occurs within the liver and causes liver inflammation. The models presented here are valuable to investigate the priming of T-cells in the liver and their role in the development of autoimmune disease of the liver.