...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens
【24h】

Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens

机译：胸腺克隆缺失过程中，促凋亡蛋白Bim与普遍存在的组织限制性抗原不同

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Positive and negative selection of thymocytes in the thymus are critical for the development of a mature and self-tolerant T-cell repertoire. The proapoptotic Bcl-2 family member Bim is important for negative selection by inducing apoptosis in thymocytes receiving a strong signal through their antigen receptor. However, in the case of ubiquitous self-antigens (UbA), Bim is not required for the clonal deletion of self-reactive thymocytes, suggesting the existence of nonapoptotic clonal deletion mechanisms. Unlike UbA, clonal deletion to tissue-restricted antigens (TRAs) requires positive selection and CCR7-mediated migration to the medulla. This led us to hypothesize that Bim is required for the latter. To study the role of Bim in clonal deletion to TRA, we constructed bone marrow (BM) chimeras using OT-I Bim-deficient or -sufficient donor bone marrow and recipients that express membrane bound chicken ovalbumin under control of the rat insulin promoter (Rip-mOVA). We found that clonal deletion to TRA was completely abrogated in the absence of Bim and large numbers of mature OT-I CD8 T cells survived in the periphery. Despite the large numbers of autoreactive T cells, the chimeras did not develop diabetes and OT-I Bim-deficient T cells from these chimeras were functionally impaired. Collectively, these data provide unique evidence of a differential, thymocyte-intrinsic, molecular requirement downstream of the T-cell receptor (TCR) for clonal deletion to UbA versus TRA and highlight the profound ability of other tolerance mechanisms to control T-cell autoreactivity in the absence of thymic clonal deletion.
机译：胸腺中胸腺细胞的正负选择对于成熟和自我耐受的T细胞库的发展至关重要。促凋亡的Bcl-2家族成员Bim通过诱导胸腺细胞通过其抗原受体接受强信号的凋亡，对于阴性选择非常重要。但是，在普遍存在的自身抗原（UbA）的情况下，自我反应性胸腺细胞的克隆删除不需要Bim，这表明存在非凋亡性克隆删除机制。与UbA不同，克隆到组织限制性抗原（TRAs）的过程需要阳性选择和CCR7介导的向髓质的迁移。这使我们假设后者需要Bim。为了研究Bim在TRA克隆缺失中的作用，我们使用OT-1 Bim缺失或充足的供体骨髓和在大鼠胰岛素启动子控制下表达膜结合鸡卵清蛋白的受体构建了骨髓（BM）嵌合体（Rip -mOVA）。我们发现，在缺少Bim的情况下，TRA的克隆缺失被完全消除，并且大量成熟的OT-1 CD8 T细胞在外周存活。尽管自身反应性T细胞数量众多，但嵌合体并未发展为糖尿病，这些嵌合体的OT-1 Bim缺陷T细胞功能受损。总的来说，这些数据提供了独特的证据，证明在T细胞受体（TCR）下游需要相对于TRA克隆删除UbA的差异性胸腺细胞内在分子需求，并突显了其他耐受机制在控制T细胞自身反应性方面的强大能力。没有胸腺克隆缺失。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号