Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.
Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.
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DOI：
10.1038/ni.2292
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发表时间：
2012-04-29
影响因子：
30.5
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中科院分区：
文献类型：
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自身反应性胸腺细胞的克隆缺失对于自身耐受是重要的，但是诱导克隆缺失的胸腺内信号尚未被清楚地鉴定。我们现在报告，克隆删除在负选择需要CD 28共刺激的自身反应性胸腺细胞在CD 4 + CD 8lo分化的中间阶段。通过不存在CD 28共刺激或抗凋亡因子Bcl-2或Mcl-1的转基因过表达来防止自身反应性胸腺细胞发生克隆缺失，存活的胸腺细胞分化为无反应性T细胞受体αβ+双阴性胸腺细胞，其优先迁移到肠道，在那里它们重新表达CD 8 α并作为CD 8 αα上皮内淋巴细胞（IEL）被隔离。本研究将CD 28共刺激确定为克隆缺失所需的胸腺内信号，并将CD 8 αα IEL确定为在阴性选择中存活的自身反应性胸腺细胞的发育命运。
Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intra-thymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection requires CD28 costimulation of autoreactive thymocytes at the CD4+CD8lo intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either absent CD28 costimulation or transgenic over-expression of the anti-apoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic T cell receptor αβ+ double negative thymocytes that preferentially migrated to the intestine where they re-expressed CD8α and were sequestered as CD8αα intraepithelial lymphocytes (IELs). This study identifies CD28 costimulation as the intrathymic signal required for clonal deletion and identifies CD8αα IELs as the developmental fate of autoreactive thymocytes that survive negative selection.