Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21
Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21
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DOI：
10.1038/ni1209x
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发表时间：
2005-07-01
影响因子：
30.5
通讯作者：
Osborne, BA
中科院分区：
文献类型：
--
作者：
Minter, LM;Turley, DM;Osborne, BA
Notch受体是由伽马神分泌酶与T细胞受体信号传导作用以维持外周T细胞活化的协同作用的。活化的CD4（+）T细胞分化为T辅助器1型（T（H）1）或T（H）2子集。指导Th1分化的分子提示包括由TBX21编码的T（H）1特异性转录因子T-BET的表达。但是，TBX21的调节仍未完全定义。在这里，我们报告说Notch1可以通过TBX21启动子上形成的复合物直接调节TBX21。在体外，γ-分泌酶抑制剂在T（H）1极化CD4（+）细胞中熄灭了Notch，干扰素 - 伽马和TBX21的表达，而活化Notch1的异位表达恢复了TBX21转录。在体内，在小鼠实验性自身免疫性脑脊髓炎模型的多发性硬化症的小鼠实验性自身免疫性脑脊髓炎模型中，施用γ-分泌酶抑制剂极大地阻碍了T（H）1介导的疾病进展。因此，使用γ-分泌酶抑制剂调节Notch信号传导可能会证明有益于治疗t（H）1介导的自身免疫性。
Notch receptors are processed by gamma secretase acting in synergy with T cell receptor signaling to sustain peripheral T cell activation. Activated CD4(+) T cells differentiate into T helper type 1 ( T(H)1) or T(H)2 subsets. Molecular cues directing TH1 differentiation include expression of the T(H)1-specific transcription factor T-bet, encoded by Tbx21. However, the regulation of Tbx21 remains incompletely defined. Here we report that Notch1 can directly regulate Tbx21 through complexes formed on the Tbx21 promoter. In vitro, gamma-secretase inhibitors extinguished expression of Notch, interferon-gamma and Tbx21 in T(H)1-polarized CD4(+) cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of gamma-secretase inhibitors substantially impeded T(H)1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using gamma-secretase inhibitors to modulate Notch signaling may prove beneficial in treating T(H)1-mediated autoimmunity.