CCR7 on CD4+ T Cells Plays a Crucial Role in the Induction of Experimental Autoimmune Encephalomyelitis
CCR7 on CD4+ T Cells Plays a Crucial Role in the Induction of Experimental Autoimmune Encephalomyelitis
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DOI：
10.4049/jimmunol.1701419
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发表时间：
2018-04-15
影响因子：
4.4
通讯作者：
Siffrin, Volker
中科院分区：
文献类型：
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作者：
Belikan, Patrick;Buelller, Ulrike;Siffrin, Volker
多发性硬化（MS）是中枢神经系统最常见的慢性炎性脱髓鞘疾病。髓磷脂特异性CD 4（+）Th淋巴细胞在MS及其实验性自身免疫性脑脊髓炎（EAE）动物模型中起重要作用。CCR 7是在稳态条件下免疫细胞运输和再循环（即淋巴结归巢）的关键元件;阻断CCR 7（+）中枢记忆细胞从淋巴结流出是MS的一种治疗方法。为了确定CCR 7的CD 4（+）T细胞特异性组成型缺失在EAE的引发和效应期的作用，我们在T细胞重建的Rag 1（-/-）小鼠以及过继转移EAE中使用了主动EAE方法，其中小鼠接受体外致敏的CCR 7（-/-）或CCR 7（+）/（+）髓鞘Ag TCR转基因2d 2 Th 17细胞。在活体麻醉小鼠中应用双光子激光扫描显微镜来监测CNS内炎性病变中CCR 7缺陷型和野生型CD 4（+）T细胞的运输。我们证明，CD 4（+）T细胞特异性组成性缺失CCR 7导致活动性EAE的诱导受损。在过继转移EAE中，接受体外致敏的CCR 7（-/-）2d 2 Th 17细胞的小鼠显示出与过继转移CCR 7（+）/（+）2d 2 Th 17细胞的小鼠相似的疾病发作。使用双光子激光扫描显微镜，CCR 7（-/-）和CCR 7（+）/（+）CD 4（+）T细胞在MS的动物模型中的运动性没有显示差异。这些发现表明，在自身免疫CD 4（+）T细胞的引发过程中，CCR 7在神经炎症中起着至关重要的作用，但在中枢神经系统中却没有。
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Myelin-specific CD4(+) Th lymphocytes are known to play a major role in both MS and its animal model experimental autoimmune encephalomyelitis (EAE). CCR7 is a critical element for immune cell trafficking and recirculation, that is, lymph node homing, under homeostatic conditions; blocking CCR7(+) central memory cells from egress of lymph nodes is a therapeutic approach in MS. To define the effect of CD4(+) T cell-specific constitutive deletion of CCR7 in the priming and effector phase in EAE, we used an active EAE approach in T cell reconstituted Rag1(-/-) mice, as well as adoptive transfer EAE, in which mice received in vitro-primed CCR7(-/-) or CCR7(+)/(+) myelin Ag TCR-transgenic 2d2 Th17 cells. Two-photon laser scanning microscopy was applied in living anesthetized mice to monitor the trafficking of CCR7-deficient and wild-type CD4(+) T cells in inflammatory lesions within the CNS. We demonstrate that CD4(+) T cell-specific constitutive deletion of CCR7 led to impaired induction of active EAE. In adoptive transfer EAE, mice receiving in vitro-primed CCR7(-/-) 2d2 Th17 cells showed similar disease onset as mice adoptively transferred with CCR7(+)/(+) 2d2 Th17 cells. Using two-photon laser scanning microscopy CCR7(-/-) and CCR7(+)/(+) CD4(+) T cells did not reveal differences in motility in either animal model of MS. These findings indicate a crucial role of CCR7 in neuroinflammation during the priming of autoimmune CD4(+) T cells but not in the CNS.