Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase Cθ and attenuates experimental autoimmune encephalomyelitis
Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase Cθ and attenuates experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.180.4.2634
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Selmaj, Krzysztof
中科院分区：
文献类型：
--
作者：
Jurynczyk, Maciej;Jurewicz, Anna;Selmaj, Krzysztof
在其多种功能中，Notch信号参与外周T细胞反应。CD4(+) T细胞向Th1谱系的激活和极化是多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎发病的重要步骤。用γ分泌酶抑制剂抑制所有四种Notch受体可阻断th1型极化并减轻实验性自身免疫性脑脊髓炎的症状。在这项研究中，我们研究了单个Notch受体在plp反应性T细胞增殖、细胞因子产生和致脑潜能中的作用。在Ag刺激下，plp反应性T细胞特异性诱导Notch1和Notch3转录物。然而，使用γ -分泌酶抑制剂和Abs阻断不同的Notch受体，我们发现选择性抑制Notch3而非Notch1受体可抑制plp反应性T细胞的增殖、Th1-和th17型反应。此外，Notch3在T细胞中的抑制与蛋白激酶CO的表达下调相关，蛋白激酶CO在成熟T细胞中具有重要的调节功能。因此，选择性抑制Notch3受体可能对外周T细胞反应有重要影响，并可能为治疗自身免疫性疾病（包括多发性硬化症）提供一个新的有吸引力的靶点。
Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4(+) T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a gamma-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using gamma-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase CO, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.