Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells
Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells
复制标题
DOI：
10.4049/jimmunol.0902797
复制
发表时间：
2010-11-01
影响因子：
4.4
通讯作者：
Senju, Satoru
中科院分区：
文献类型：
--
作者：
Ikeda, Tokunori;Hirata, Shinya;Senju, Satoru
已知TRAIL在抑制自身免疫性疾病中起关键作用。我们以前证明，树突状细胞的管理工程表达TRAIL和髓鞘少突胶质细胞糖蛋白降低了实验性自身免疫性脑脊髓炎的严重程度，并建议，CD 4（+）CD 25（+）调节性T细胞（T细胞）参与介导这种预防作用。在目前的研究中，我们使用TRAIL缺陷小鼠研究了TRAIL对T细胞以及常规T细胞的影响。在诱导实验性自身免疫性脑脊髓炎后，与野生型小鼠相比，TRAIL缺陷小鼠表现出更严重的临床症状、产生IFN-γ的CD 4（+）T（Th 1）细胞的频率更高，而CD 4（+）Foxp 3（+）Tregs的频率更低。在体外，传统的T细胞刺激骨髓来源的树突状细胞（BM-DCs）从TRAIL缺陷型小鼠表现出更大幅度的增殖比刺激BM-DCs从野生型小鼠。相反，在刺激BM-DCs上表达的TRAIL增强了培养物中CD 4（+）CD 25（+）T细胞的增殖反应。功能性TRAILR，小鼠死亡受体5（mDR 5），在刺激后在常规T细胞和TCF 4中表达。相比之下，诱饵受体mDc-TRAILR 1仅在CD 4（+）CD 25（+）T细胞上轻微表达。因此，TRAIL的不同作用可能是由于两种T细胞亚群之间mDc-TRAILR 1表达或小鼠死亡受体5下游信号通路的差异。我们的数据表明，TRAIL通过两种机制抑制自身免疫：抑制Th 1细胞和促进T细胞活化。免疫学杂志，2010，185：5259-5267。
TRAIL is known to play a pivotal role in the inhibition of autoimmune disease. We previously demonstrated that administration of dendritic cells engineered to express TRAIL and myelin-oligodendrocyte glycoprotein reduced the severity of experimental autoimmune encephalomyelitis and suggested that CD4(+)CD25(+) regulatory T cells (Tregs) were involved in mediating this preventive effect. In the current study, we investigated the effect of TRAIL on Tregs, as well as conventional T cells, using TRAIL-deficient mice. Upon induction of experimental autoimmune encephalomyelitis, TRAIL-deficient mice showed more severe clinical symptoms, a greater frequency of IFN-gamma-producing CD4(+) T (Th1) cells, and a lower frequency of CD4(+)Foxp3(+) Tregs than did wild-type mice. In vitro, conventional T cells stimulated by bone marrow-derived dendritic cells (BM-DCs) from TRAIL-deficient mice showed a greater magnitude of proliferation than did those stimulated by BM-DCs from wild-type mice. In contrast, TRAIL expressed on the stimulator BM-DCs enhanced the proliferative response of CD4(+)CD25(+) Tregs in the culture. The functional TRAILR, mouse death receptor 5 (mDR5), was expressed in conventional T cells and Tregs upon stimulation. In contrast, the decoy receptor, mDc-TRAILR1, was slightly expressed only on CD4(+)CD25(+) Tregs. Therefore, the distinct effects of TRAIL may be due to differences in the mDc-TRAILR1 expression or the signaling pathways downstream of mouse death receptor 5 between the two T cell subsets. Our data suggest that TRAIL suppresses autoimmunity by two mechanisms: the inhibition of Th1 cells and the promotion of Tregs. The Journal of Immunology, 2010, 185: 5259-5267.