Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China.
Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
Chin Med J (Engl). 2019 Dec 20;132(24):2934-2940. doi: 10.1097/CM9.0000000000000551.
BACKGROUND: The pathogenesis of multiple sclerosis (MS) is mediated primarily by T cells, but most studies of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have focused on CD4 T cells. The aims of the current study were to determine the pathological interrelationship between CD4 and CD8 autoreactive T cells in MS/EAE. METHODS: Female C57BL/6 mice (n = 20) were induced by myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. At 14 days after immunization, T cells were isolated from the spleen and purified as CD4 and CD8 T cells by using CD4 and CD8 isolation kits, and then the purity was determined by flow cytometric analysis. These cells were stimulated by MOG35-55 peptide and applied to proliferation assays. The interferon-gamma (IFN-γ) and interleukin (IL)-4 secretion of supernatant of cultured CD4 and CD8 T cells were measured by enzyme-linked immunosorbent assays (ELISA). For adoptive transfer, recipient mice were injected with MOG35-55-specific CD8 or CD4 T cells. EAE clinical course was measured by EAE score at 0-5 scale and spinal cord was examined by staining with hematoxylin and eosin and Luxol fast blue staining. RESULTS: CD8CD3 and CD4CD3 cells were 86% and 94% pure of total CD3 cells after CD8/CD4 bead enrichment, respectively. These cells were stimulated by MOG35-55 peptide and applied to proliferation assays. Although the CD8 T cells had a generally lower response to MOG35-55 than CD4 T cells, the response of CD8 T cells was not always dependent on CD4. CD8 T cell secreted less IFN-γ and IL-4 compared with CD4 T cells. EAE was induced in wildtype B6 naïve mice by adoptive transfer of MOG35-55-specific T cells from B6 active-induced EAE (aEAE) mice. A similar EAE score and slight inflammation and demyelination were found in naive B6 mice after transferring of CD8 T cells from immunized B6 mice compared with transfer of CD4 T cells. CONCLUSION: Our data suggest that CD8 autoreactive T cells in EAE have a lower encephalitogenic function but are unique and independent on pathogenic of EAE rather than their CD4 counterparts.
背景：多发性硬化症（MS）的发病机制主要由 T 细胞介导，但对 MS 及其动物模型实验性自身免疫性脑脊髓炎（EAE）的大多数研究都集中在 CD4 T 细胞上。本研究的目的是确定 MS/EAE 中 CD4 和 CD8 自身反应性 T 细胞之间的病理相互关系。
方法：雌性 C57BL/6 小鼠（n=20）用髓鞘少突胶质细胞糖蛋白（MOG）35-55 肽诱导。免疫后 14 天，从脾脏中分离 T 细胞，并通过 CD4 和 CD8 分离试剂盒将其纯化为 CD4 和 CD8 T 细胞，然后通过流式细胞术分析确定纯度。用 MOG35-55 肽刺激这些细胞，并进行增殖实验。通过酶联免疫吸附试验（ELISA）测量培养的 CD4 和 CD8 T 细胞上清液中干扰素-γ（IFN-γ）和白细胞介素（IL）-4 的分泌。用于过继转移，受者小鼠注射 MOG35-55 特异性 CD8 或 CD4 T 细胞。EAE 临床病程通过 0-5 刻度的 EAE 评分测量，并用苏木精和伊红染色以及卢索快速蓝染色检查脊髓。
结果：用 CD8/CD4 珠富集后，CD8CD3 和 CD4CD3 细胞分别为总 CD3 细胞的 86%和 94%纯。这些细胞用 MOG35-55 肽刺激并进行增殖实验。尽管 CD8 T 细胞对 MOG35-55 的反应通常低于 CD4 T 细胞，但 CD8 T 细胞的反应并不总是依赖于 CD4。与 CD4 T 细胞相比，CD8 T 细胞分泌的 IFN-γ 和 IL-4 较少。通过从免疫 B6 小鼠中过继转移 MOG35-55 特异性 T 细胞，在野生型 B6 小鼠中诱导 EAE。与转移 CD4 T 细胞相比，从免疫 B6 小鼠中转移 CD8 T 细胞后，幼稚 B6 小鼠中发现了类似的 EAE 评分以及轻微的炎症和脱髓鞘。
结论：我们的数据表明，EAE 中的 CD8 自身反应性 T 细胞具有较低的脑炎发病功能，但与 CD4 对应物不同，它们具有独特性和独立性，而不是其致病性。
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