Mehal W Z, Azzaroli F, Crispe I N
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
J Immunol. 2001 Jul 15;167(2):667-73. doi: 10.4049/jimmunol.167.2.667.
Systemic activation and proliferation of CD8(+) T cells result in T cell accumulation in the liver, associated with T cell apoptosis and liver injury. However, the role of Ag and APC in such accumulation is not clear. Bone marrow chimeras were constructed to allow Ag presentation in all tissues or alternatively to restrict presentation to either bone marrow-derived or non-bone marrow-derived cells. OVA-specific CD8(+) T cells were introduced by adoptive transfer and then activated using peptide, which resulted in clonal expansion followed by deletion. Ag presentation by liver non-bone marrow-derived cells was responsible for most of the accumulation of activated CD8(+) T cells. In contrast, Ag presentation by bone marrow-derived cells resulted in less accumulation of T cells in the liver, but a higher frequency of apoptotic cells within the intrahepatic T cell population. In unmodified TCR-transgenic mice, Ag-induced T cell deletion and intrahepatic accumulation of CD8(+) T cells result in hepatocyte damage, with the release of aminotransaminases. Our experiments show that such liver injury may occur in the absence of Ag presentation by the hepatocytes themselves, arguing for an indirect mechanism of liver damage.
CD8(+) T细胞的全身激活和增殖导致T细胞在肝脏中积聚，这与T细胞凋亡和肝损伤相关。然而，抗原（Ag）和抗原呈递细胞（APC）在这种积聚中的作用尚不清楚。构建骨髓嵌合体以实现抗原在所有组织中的呈递，或者将呈递限制于骨髓来源的细胞或非骨髓来源的细胞。通过过继转移引入卵清蛋白（OVA）特异性CD8(+) T细胞，然后用肽激活，这导致克隆扩增随后发生缺失。肝脏非骨髓来源细胞的抗原呈递是活化的CD8(+) T细胞大部分积聚的原因。相比之下，骨髓来源细胞的抗原呈递导致肝脏中T细胞的积聚较少，但肝内T细胞群体中凋亡细胞的频率较高。在未修饰的T细胞受体转基因小鼠中，抗原诱导的T细胞缺失和CD8(+) T细胞在肝内的积聚导致肝细胞损伤，并伴有转氨酶的释放。我们的实验表明，这种肝损伤可能在肝细胞自身不进行抗原呈递的情况下发生，这表明肝损伤存在间接机制。
