Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Multiple Sclerosis Clinic, Division of Neurology, Centre Hospitalier de l'Université de Montréal (CHUM)-Notre Dame Hospital, Montreal, Quebec, Canada.
Ann Neurol. 2015 Jul;78(1):39-53. doi: 10.1002/ana.24415. Epub 2015 May 20.
Although 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.
Frequency, 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.
Herein, 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 γ, 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.
Our 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.
尽管 Tc17 淋巴细胞在多发性硬化症（MS）患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）中丰富，但关于它们进入 CNS 的募集及其在神经炎症中的作用的信息有限。鉴定自身反应性 CD8(+) T 淋巴细胞进入 CNS 所使用的粘附分子将允许进一步表征这种致病亚群，并为 MS 提供新的治疗靶点。我们提出黑色素瘤细胞粘附分子（MCAM）是一种表面标志物和粘附分子，用于致病性 CD8(+) T 淋巴细胞进入 CNS。
使用体外、体内、原位和体内方法的组合，包括健康对照、MS 患者和 EAE 动物，对 MCAM(+) CD8(+) T 淋巴细胞的频率、表型和功能进行了表征。
在此，我们报告 MCAM 由人类效应 CD8(+) T 淋巴细胞表达，并且在 MS 复发期间显著上调。我们进一步证明 MCAM(+) CD8(+) T 淋巴细胞表达更多的白细胞介素 17、干扰素 γ、粒细胞-巨噬细胞集落刺激因子和肿瘤坏死因子，比 MCAM(-) 淋巴细胞，并且对少突胶质细胞具有增强的杀伤能力。MCAM 阻断在体外限制 CD8(+) 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 可减少活跃、转移和自发进展性 EAE 模型中的慢性神经缺陷。
我们的数据表明，MCAM 鉴定出致脑炎性 CD8(+) T 淋巴细胞，表明 MCAM 可能是 MS 疾病活动的生物标志物和神经炎症状况治疗的有效靶点。
