Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling
Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling
复制标题
DOI：
10.1053/j.gastro.2008.06.042
复制
发表时间：
2008-10-01
期刊：
影响因子：
29.4
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Kido, Masahiro;Watanabe, Norihiko;Chiba, Tsutomu
背景和目标：由于缺乏自发性自身免疫性肝炎（AIH）的动物模型，AIH发生发展的分子机制尚不清楚。本研究旨在探讨自然产生的CD 4（+）CD 25（+）调节性T（Treg）细胞和程序性细胞死亡1（PD-1）介导的信号转导在AIH发生发展中的调节作用。研究方法：为了诱导Treg细胞和PD-1介导的信号传导的同时损失，对PD-1（-/-）小鼠进行严重减少Treg细胞数量的新生儿胸腺切除术（NTx）。NTx后，我们进行组织学检查，评估自身抗体的产生和浸润细胞在肝脏中，并进行过继转移实验。结果如下：与NTx小鼠和PD-1（-/-）小鼠相反，NTx-PD-1（-/-）小鼠产生抗核抗体并发生致命性肝炎，其特征为CD 4（+）和CD 8（+）T细胞浸润侵入实质，伴大面积小叶坏死。NTx-PD-1（-/-）小鼠中AIH的诱导被Treg细胞的转移所抑制，甚至来自PD-1（-/-）小鼠。将NTx-PD-1（-/-）小鼠的全部但非CD 4（+）T细胞耗竭的脾细胞转移到RAG 2（-/-）小鼠中诱导了重度肝炎的发生。相反，CD 8（+）T细胞耗竭的脾细胞的转移仅引发单核细胞浸润，而没有实质的大量坏死。结论：NTx-PD-1（-/-）小鼠是第一个自发致死性AIH小鼠模型。Treg细胞和PD-1介导的信号传导的同时丧失可诱导致命性AIH的发展。自身反应性CD 4（+）T细胞在AIH的诱导过程中是必不可少的，而CD 8（+）T细胞在致命性肝损伤的进展中起重要作用。
Background & Aims: Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. Methods: To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. Results: In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. in contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. Conclusions: NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.