Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease
Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease
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DOI：
10.4049/jimmunol.177.7.4281
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Azuma, Miyuki
中科院分区：
文献类型：
--
作者：
Oikawa, Tsunekazu;Kamimura, Yosuke;Azuma, Miyuki
Tim-3是T细胞IG粘蛋白（TIM）家族的成员，调节效应器Th 1应答。我们在急性移植物抗宿主病（aGVHD）的鼠模型中检查了Tim-3及其配体表达以及抗Tim-3 mAb治疗的效果。在患有aGVHD的小鼠中，脾脏和肝脏CD 4（+）和CD 8（+）T细胞、树突状细胞（DC）和巨噬细胞上的Tim-3表达显著上调，并且这在肝脏CD 8（+）T细胞中尤其显著。供体和宿主来源的CD 8（+）T细胞诱导相似水平的Tim-3。Tim-3配体的表达在脾T细胞、DC和巨噬细胞中也上调，但在肝淋巴细胞中没有。抗Tim-3 mAb的施用加速aGVHD，如通过体重减轻、总脾细胞数量减少和肝脏中淋巴细胞浸润所证明的。抗Tim-3单克隆抗体处理显著增强脾和肝CD 4（+）和CD 8（+）T细胞的IFN-γ表达。此外，供体CD 8（+）T细胞对宿主同种异体抗原的细胞毒性增强。这些结果表明，aGVHD中的抗Tim-3处理增强了表达IFN-γ或发挥细胞毒性的效应T细胞的活化。我们的研究结果表明，Tim-3可能在调节负责维持肝脏稳态和耐受的CD 8（+）T细胞中起着至关重要的作用。
Tim-3, a member of the T cell Ig mucin (TIM) family regulates effector Th1 responses. We examined Tim-3 and its ligand expression as well as the effects of anti-Tim-3 mAb treatment in a murine model of acute graft-vs-host disease (aGVHD). In mice with aGVHD, Tim-3 expression was markedly up-regulated on splenic and hepatic CD4(+) and CD8(+) T cells, dendritic cells (DCs), and macrophages, and this was especially dramatic in hepatic CD8(+) T cells. Both donor- and host-derived CD8(+) T cells induced similar levels of Tim-3. Tim-3 ligand expression was also up-regulated in splenic T cells, DCs, and macrophages, but not in the hepatic lymphocytes. The administration of anti-Tim-3 mAbs accelerated aGVHD, as demonstrated by body weight loss, reduction in total splenocyte number, and infiltration of lymphocytes in the liver. IFN-gamma expression by splenic and hepatic CD4(+) and CD8(+) T cells was significantly augmented by anti-Tim-3 mAb treatment. In addition, the cytotoxicity against host alloantigen by donor CD8(+) T cells was enhanced. These results demonstrate that the anti-Tim-3 treatment in aGVHD augmented the activation of effector T cells expressing IFN-gamma or exerting cytotoxicity. Our results suggest that Tim-3 may play a crucial role in the regulation of CD8(+) T cells responsible for the maintenance of hepatic homeostasis and tolerance.