Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.
Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.
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DOI：
10.4049/jimmunol.1301116
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发表时间：
2013-08-15
期刊：
影响因子：
--
通讯作者：
Maillard I
中科院分区：
文献类型：
--
作者：
Sandy AR;Stoolman J;Malott K;Pongtornpipat P;Segal BM;Maillard I
Notch信号传导的系统性抑制先前显示减弱实验性自身免疫性脑脊髓炎（EAE），一种小鼠多发性硬化症的疾病模型。不同的研究将这些作用归因于T-bet和IFNγ表达降低、调节性T细胞功能增强、T细胞对中枢神经系统（CNS）的趋化性降低或Th 9细胞分化受损。这些异质性发现的解释是困难的，因为过去的实验策略不能确保T细胞中的完全Notch抑制，并且因为许多细胞群可能受到全身性Notch阻断的影响。为了解决Notch在EAE期间T细胞中的作用，我们使用了泛Notch抑制剂Mastermind样1（DNMAML）的显性阴性形式，以及几种互补的功能丧失方法，特别是在髓鞘反应性T细胞中。T细胞中的Notch抑制显著降低EAE的发生率和严重程度。Notch-deprived髓鞘反应性T细胞在次级淋巴组织中保留了活化和效应分化。然而，Notch剥夺的T细胞未能在免疫后的CNS中积累。将野生型和DNMAML T细胞一起停放在骨髓嵌合体中增加了免疫后CNS中Notch剥夺T细胞的积累，但没有预防EAE，表明DNMAML T细胞不存在显性抑制。CNS浸润性DNMAML T细胞的分析显示，尽管保留了T-bet表达，但IL-17 A和IFNγ产生明显缺陷。总而言之，我们的研究结果捕获了Notch信号在髓鞘反应性T细胞中的深刻的整体影响，并证明Notch控制了EAE期间CD 4 + T细胞在其靶器官中的积累和致病功能，但不在淋巴组织中。
Systemic inhibition of Notch signaling was previously shown to attenuate experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis in mice. Different studies attributed these effects to decreased T-bet and IFNγ expression, enhanced regulatory T cell function, reduced T cell chemotaxis to the central nervous system (CNS) or impaired Th9 cell differentiation. Interpretation of these heterogeneous findings is difficult, since past experimental strategies did not ensure complete Notch inhibition in T cells and since many cell populations could be affected by systemic Notch blockade. To resolve the role of Notch in T cells during EAE, we used the pan-Notch inhibitor dominant negative form of Mastermind-like 1 (DNMAML), as well as several complementary loss-of-function approaches specifically in myelin-reactive T cells. Notch inhibition in T cells profoundly decreased EAE incidence and severity. Notch-deprived myelin-reactive T cells had preserved activation and effector differentiation in secondary lymphoid tissues. However, Notch-deprived T cells failed to accumulate in the CNS post-immunization. Parking wild type and DNMAML T cells together in bone marrow chimeras increased accumulation of Notch-deprived T cells in the CNS post-immunization but did not prevent EAE, indicating the absence of dominant suppression by DNMAML T cells. Analysis of CNS-infiltrating DNMAML T cells revealed markedly defective IL-17A and IFNγ production, despite preserved T-bet expression. Altogether, our findings capture the profound overall effects of Notch signaling in myelin-reactive T cells and demonstrate that Notch controls the accumulation and pathogenic functions of CD4+ T cells within their target organ but not in lymphoid tissues during EAE.
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影响因子：
4.4
作者：
Jurynczyk, Maciej;Jurewicz, Anna;Selmaj, Krzysztof
通讯作者：
Selmaj, Krzysztof
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
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影响因子：
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Jurynczyk, M;Jurewicz, A;Selmaj, K
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Selmaj, K
影响因子：
30.5
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影响因子：
2.5
作者：
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