CNS-resident classical DCs play a critical role in CNS autoimmune disease
CNS-resident classical DCs play a critical role in CNS autoimmune disease
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CNS驻留的经典DC在CNS自身免疫性疾病中起关键作用
DOI：
10.1172/jci123708
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发表时间：
2018-12-03
影响因子：
15.9
通讯作者：
Segal, Benjamin M.
中科院分区：
文献类型：
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作者：
Giles, David A.;Duncker, Patrick C.;Segal, Benjamin M.
实验性自身免疫性脑脊髓炎（Experimental autoimmune encephalomyelitis，EAE）是由髓磷脂反应性CD 4（+）T细胞过继性转移到同基因小鼠体内引起的中枢神经系统炎性脱髓鞘疾病。它被广泛用作多发性硬化症（MS）的啮齿动物模型。当转移的CD 4（+）T细胞进入CNS并被携带内源性髓鞘肽/MHC II类复合物的局部抗原呈递细胞（APC）重新激活时，EAE病变的发展开始。CNS驻留、病变启动APC的身份存在广泛争议。在这里，我们证明了经典的树突状细胞（cDCs）通常驻留在脑膜，大脑和脊髓中的稳定状态。这些细胞在候选CNS APC中是独特的，因为它们能够刺激幼稚的以及效应的髓鞘特异性T细胞增殖并直接离体产生促炎细胞因子。cDC在脑膜和CNS实质中扩增与疾病进展相关。cDC的选择性消耗导致CNS中髓鞘致敏的供体T细胞的数量减少，并将临床EAE的发病率降低一半。基于我们的研究结果，我们建议将cDC及其调节因子作为MS的潜在治疗靶点进行进一步研究。
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), induced by the adoptive transfer of myelin-reactive CD4(+) T cells into naive syngeneic mice. It is widely used as a rodent model of multiple sclerosis (MS). The development of EAE lesions is initiated when transferred CD4(+) T cells access the CNS and are reactivated by local antigen-presenting cells (APCs) bearing endogenous myelin peptide/MHC class II complexes. The identity of the CNS-resident, lesion-initiating APCs is widely debated. Here we demonstrate that classical dendritic cells (cDCs) normally reside in the meninges, brain, and spinal cord in the steady state. These cells are unique among candidate CNS APCs in their ability to stimulate naive, as well as effector, myelin-specific T cells to proliferate and produce proinflammatory cytokines directly ex vivo. cDCs expanded in the meninges and CNS parenchyma in association with disease progression. Selective depletion of cDCs led to a decrease in the number of myelin-primed donor T cells in the CNS and reduced the incidence of clinical EAE by half. Based on our findings, we propose that cDCs, and the factors that regulate them, be further investigated as potential therapeutic targets in MS.