Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice
Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice
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DOI：
10.1002/hep.20204
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发表时间：
2004-05-01
期刊：
影响因子：
13.5
通讯作者：
Asahara, T
中科院分区：
文献类型：
--
作者：
Ochi, M;Ohdan, H;Asahara, T
尽管已知自然杀伤（NK）细胞的激活导致肝损伤，但NK细胞诱导的自身肝细胞杀伤的潜在机制尚不清楚。我们证明了肝脏NK细胞对小鼠正常同系肝细胞具有细胞毒性。聚肌胞苷酸（聚I：C）治疗增强肝NK细胞的肝细胞毒性，但不是脾NK细胞。与其他组织中的NK细胞不同，大约30%-40%的肝脏NK细胞组成性表达肿瘤坏死因子相关凋亡诱导配体（TRAIL）。体外NK细胞毒性试验显示，肝细胞毒性的肝脏NK细胞从幼稚和聚I：C处理的小鼠被抑制部分由抗TRAIL单克隆抗体（mAb）单独和完全由抗Fas配体（FasL）mAb和穿孔素抑制剂，康卡那霉素A的组合，表明贡献的TRAIL NK细胞介导的肝细胞毒性。大多数TRAIL（+）NK细胞缺乏识别自身主要组织相容性复合物I类的Ly-49抑制性受体的表达，表明其倾向于靶向自身肝细胞。Poly I：C处理显著上调TRAIL（-）NK细胞上Ly-49受体的表达。这可能是一种补偿机制，以保护自身I类表达细胞免受激活的NK细胞介导的杀伤。然而，在TRAIL（+）NK细胞部分中根本没有看到这种代偿性改变。因此，肝脏TRAIL（+）NK细胞的自我识别能力较低，这可能与NK细胞依赖性自身肝细胞毒性有关。总之，我们的研究结果与表达TRAIL的NK细胞通过对MHC识别不良在自身肝细胞杀伤中发挥关键作用的模型一致。
Although it is known that activation of natural killer (NK) cells causes liver injury, the mechanisms underlying NK cell-induced killing of self-hepatocytes are not dear. We demonstrated that liver NK cells have cytotoxicity against normal syngeneic hepatocytes in mice. Polyinosinic-polycytidylic acid (poly I:C) treatment enhanced hepatocyte toxicity of liver NK cells but not that of spleen NK cells. Unlike NK cells in other tissues, approximately 30%-40% of liver NK cells constitutively express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). An in vitro NK cell cytotoxic assay revealed that hepatocyte toxicity of liver NK cells from both naive and poly I:C-treated mice was inhibited partially by an anti-TRAIL monoclonal antibody (mAb) alone and completely by the combination with anti-Fas ligand (FasL) mAb and a perforin inhibitor, concanamycin A, indicating contribution of TRAIL to NK cell-mediated hepatocyte toxicity. The majority of TRAIL(+) NK cells lacked expression of Ly-49 inhibitory receptors recognizing self-major histocompatibility complex class I, indicating a propensity to targeting self-hepatocytes. Poly I:C treatment significantly upregulated the expression of Ly-49 receptors on TRAIL(-) NK cells. This might be a compensatory mechanism to protect self-class I-expressing cells from activated NK cell-mediated killing. However, such compensatory alteration was not seen at all in the TRAIL(+) NK cell fraction. Thus, liver TRAIL(+) NK cells have less capacity for self-recognition, and this might be involved in NK cell-dependent self-hepatocyte toxicity. In conclusion, our findings are consistent with a model in which TRAIL-expressing NK cells play a critical role in self-hepatocyte killing through poor recognition of MHC.