Tsuchida T, Parker K C, Turner R V, McFarland H F, Coligan J E, Biddison W E
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10859-63. doi: 10.1073/pnas.91.23.10859.
Identification of the targets of autoreactive T cells is important for understanding the pathogenesis of many autoimmune diseases. In multiple sclerosis, myelin proteins are thought to be the targets of autoreactive T-cell responses. To date only major histocompatibility complex class II-restricted CD4+ T-cell responses to myelin proteins have been investigated. In the present study, the ability of self peptides derived from human myelin proteins to induce autoreactive CD8+ T-cell responses has been assessed. Peptide sequences from human myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein have been identified that bind to and form stable complexes with HLA-A2. MBP 110-118, PLP 80-88, MAG 287-295, MAG 509-517, and MAG 556-564 were all able to induce peptide-specific HLA-A2-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses in vitro in HLA-A2+ individuals. CTLs specific for MBP 110-118 and MAG 556-564 could recognize endogenously processed antigens presented by HLA-A2. CTL clones reactive to MBP 110-118 and MAG 556-564 produced tumor necrosis factor alpha and a subset of these clones also produced interferon gamma. These results demonstrate that (i) self peptides derived from human myelin proteins can induce autoreactive CD8+ CTLs and (ii) these CD8+ T cells produce cytokines thought to be important in mediating demyelinating disease. These studies provide an experimental approach for the assessment of CD8+ T-cell responses in such autoimmune diseases.
确定自身反应性T细胞的靶标对于理解许多自身免疫性疾病的发病机制至关重要。在多发性硬化症中，髓磷脂蛋白被认为是自身反应性T细胞应答的靶标。迄今为止，仅研究了主要组织相容性复合体II类限制性CD4 + T细胞对髓磷脂蛋白的应答。在本研究中，评估了源自人髓磷脂蛋白的自身肽诱导自身反应性CD8 + T细胞应答的能力。已鉴定出人髓磷脂碱性蛋白（MBP）、蛋白脂蛋白（PLP）、髓磷脂相关糖蛋白（MAG）和髓磷脂少突胶质细胞糖蛋白的肽序列，这些序列可与HLA-A2结合并形成稳定的复合物。MBP 110-118、PLP 80-88、MAG 287-295、MAG 509-517和MAG 556-564均能够在体外诱导HLA-A2 +个体中肽特异性HLA-A2限制性CD8 +细胞毒性T淋巴细胞（CTL）应答。对MBP 110-118和MAG 556-564特异的CTL能够识别由HLA-A2呈递的内源性加工抗原。对MBP 110-118和MAG 556-564有反应的CTL克隆产生肿瘤坏死因子α，并且这些克隆中的一部分还产生干扰素γ。这些结果表明：（i）源自人髓磷脂蛋白的自身肽可诱导自身反应性CD8 + CTL，并且（ii）这些CD8 + T细胞产生被认为在介导脱髓鞘疾病中起重要作用的细胞因子。这些研究为评估此类自身免疫性疾病中的CD8 + T细胞应答提供了一种实验方法。
