Individual nonobese diabetic mice exhibit unique patterns of CD8+ T cell reactivity to three islet antigens, including the newly identified widely expressed dystrophia myotonica kinase
Individual nonobese diabetic mice exhibit unique patterns of CD8+ T cell reactivity to three islet antigens, including the newly identified widely expressed dystrophia myotonica kinase
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DOI：
10.4049/jimmunol.173.11.6727
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发表时间：
2004-12-01
影响因子：
4.4
通讯作者：
DiLorenzo, TP
中科院分区：
文献类型：
--
作者：
Lieberman, SM;Takaki, T;DiLorenzo, TP
NOD小鼠自发性自身免疫性糖尿病的发生需要CD 8（+）和CD 4（+）T细胞。已经描述了三种致病性CD 8（+）T细胞群体（由G9 C8、8.3和AI 4克隆代表）。虽然已知G9 C8和8.3的Ag分别是胰岛素和胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白，但先前仅鉴定了AI 4的模拟表位肽。在这项研究中，我们使用肽/MHC四聚体检测和定量这三个致病群体之间的β细胞反应性T细胞培养的胰岛个别NOD小鼠。即使在年龄匹配的组中，每只小鼠也表现出β细胞反应性CD 8（+）T细胞的独特分布，无论是四聚体染色群体的数量还是胰岛浸润中每个群体的相对比例。因此，每个人的炎症过程都遵循自己独特的过程。以位置扫描格式筛选组合肽文库导致鉴定了来源于由AI 4样T细胞识别的肌强直性肌营养不良症激酶（DMK）的肽。重要的是，抗原肽由DMK转染的细胞天然加工和呈递。DMK是一种广泛表达的蛋白质，尽管如此，它仍然是β细胞特异性自身免疫反应的靶标。
Spontaneous autoimmune diabetes development in NOD mice requires both CD8(+) and CD4(+) T cells. Three pathogenic CD8(+) T cell populations (represented by the G9C8, 8.3, and AI4 clones) have been described. Although the Ags for G9C8 and 8.3 are known to be insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein, respectively, only mimotope peptides had previously been identified for AI4. In this study, we used peptide/MHC tetramers to detect and quantify these three pathogenic populations among beta cell-reactive T cells cultured from islets of individual NOD mice. Even within age-matched groups, each individual mouse exhibited a unique distribution of beta cell-reactive CD8(+) T cells, both in terms of the number of tetramer-staining populations and the relative proportion of each population in the islet infiltrate. Thus, the inflammatory process in each individual follows its own distinctive course. Screening of a combinatorial peptide library in positional scanning format led to the identification of a peptide derived from dystrophia myotonica kinase (DMK) that is recognized by AI4-like T cells. Importantly, the antigenic peptide is naturally processed and presented by DMK-transfected cells. DMK is a widely expressed protein that is nonetheless the target of a beta cell-specific autoimmune response.