Melanoma cell adhesion molecule-positive CD8 T lymphocytes mediate central nervous system inflammation
Melanoma cell adhesion molecule-positive CD8 T lymphocytes mediate central nervous system inflammation
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DOI：
10.1002/ana.24415
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发表时间：
2015-07-01
影响因子：
11.2
通讯作者：
Prat, Alexandre
中科院分区：
文献类型：
--
作者：
Larochelle, Catherine;Lecuyer, Marc-Andre;Prat, Alexandre
尽管Tc 17淋巴细胞在多发性硬化（MS）受试者和实验性自身免疫性脑脊髓炎（EAE）动物的中枢神经系统（CNS）中富集，但关于它们在CNS中的募集及其在神经炎症中的作用的信息有限。鉴定自身侵袭性CD 8（+）T淋巴细胞进入CNS所使用的粘附分子将允许进一步表征该致病亚群，并可提供MS的新治疗靶点。我们提出黑素瘤细胞粘附分子（MCAM）是致病性CD 8（+）T淋巴细胞进入CNS所使用的表面标记物和粘附分子。和功能的MCAM（+）CD 8（+）T淋巴细胞的特点是使用组合的离体，在体外，在原位，并在人体和小鼠，包括健康对照，MS科目，和EAE animals. ResultsTherefore，我们报告说，MCAM是由人类效应CD 8（+）T淋巴细胞的表达，它是显着上调MS复发期间。我们进一步证明，MCAM（+）CD 8（+）T淋巴细胞比MCAM（-）淋巴细胞表达更多的白细胞介素17，干扰素，粒细胞-巨噬细胞集落刺激因子和肿瘤坏死因子，并表现出对少突胶质细胞的杀伤能力增强。MCAM阻断在体外限制了CD 8（+）T淋巴细胞穿过人血脑屏障内皮细胞的迁移，并且在体内阻断或耗尽MCAM减少了活动性、转移性和自发进行性EAE模型中的慢性神经功能缺损。这表明MCAM可以代表MS疾病活性的生物标志物和治疗神经炎性病症的有效靶点。《神经病学年鉴》2015;78：39-53
ObjectiveAlthough Tc17 lymphocytes are enriched in the central nervous system (CNS) of multiple sclerosis (MS) subjects and of experimental autoimmune encephalomyelitis (EAE) animals, limited information is available about their recruitment into the CNS and their role in neuroinflammation. Identification of adhesion molecules used by autoaggressive CD8(+) T lymphocytes to enter the CNS would allow further characterization of this pathogenic subset and could provide new therapeutic targets in MS. We propose that melanoma cell adhesion molecule (MCAM) is a surface marker and adhesion molecule used by pathogenic CD8(+) T lymphocytes to access the CNS.MethodsFrequency, phenotype, and function of MCAM(+)CD8(+) T lymphocytes was characterized using a combination of ex vivo, in vitro, in situ, and in vivo approaches in humans and mice, including healthy controls, MS subjects, and EAE animals.ResultsHerein, we report that MCAM is expressed by human effector CD8(+) T lymphocytes and it is strikingly upregulated during MS relapses. We further demonstrate that MCAM(+)CD8(+) T lymphocytes express more interleukin 17, interferon , granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor than MCAM(-) lymphocytes, and exhibit an enhanced killing capacity toward oligodendrocytes. MCAM blockade restricts the transmigration of CD8(+) T lymphocytes across human blood-brain barrier endothelial cells in vitro, and blocking or depleting MCAM in vivo reduces chronic neurological deficits in active, transfer, and spontaneous progressive EAE models.InterpretationOur data demonstrate that MCAM identifies encephalitogenic CD8(+) T lymphocytes, suggesting that MCAM could represent a biomarker of MS disease activity and a valid target for the treatment of neuroinflammatory conditions. Ann Neurol 2015;78:39-53