Developmental regulation of thymocyte susceptibility to deletion by "self"-peptide.
Developmental regulation of thymocyte susceptibility to deletion by "self"-peptide.
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通过“自我”肽对胸腺细胞易感性敏感性的发育调节。
DOI：
10.1084/jem.176.1.213
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发表时间：
1992-07-01
影响因子：
15.3
通讯作者：
Berg, L J
中科院分区：
文献类型：
--
作者：
Spain, L M;Berg, L J
与自身主要组织相容性复合体(MHC)分子结合的外来肽的T细胞受体(TCR)谱系的特异性在很大程度上取决于胸腺的正负选择过程，但这些选择事件的机制尚不清楚。用体外器官培养的方法，从转基因I-Ek结合细胞色素c肽TCR-α/β的小鼠胸腺中分离出胸腺，分析了负选择(缺失)的发育时机。根据下面描述的实验，我们得出结论，所有的CD4+8+胸腺细胞，只有CD4+8+胸腺细胞，都对细胞色素c肽抗原介导的负选择敏感。首先，我们发现，在胸腺器官培养中加入细胞色素c肽导致的胸腺细胞的删除可以发生在TCR、CD4和CD8共表达的最早阶段。其次，我们发现从阳性选择和非选择MHC单倍型中分离的CD4+8+胸腺细胞在体外同样有效地被删除，这表明阳性选择不是删除的先决条件。第三，我们通过改变添加到器官培养中的细胞色素c肽的浓度，研究了TCR/配体亲和力对缺失发育时间的影响。我们仅在CD4+8+阶段检测到缺失：导致CD4+8+细胞部分缺失的中等浓度的多肽并不能消除成熟的CD4+8-细胞的出现。最后，我们发现CD4+8-胸腺细胞对加入到完整器官培养物中的多肽抗原的缺失和激活具有抵抗力。然而，从经多肽处理的器官培养中分离出的CD4+8-胸腺细胞在体外对脾细胞递呈的多肽反应强烈。因此，T细胞对胸腺器官培养中遇到的自身抗原具有耐受性(但不被自身抗原激活)。综上所述，这些结果表明，对负选择敏感的胸腺细胞在发育上与对正选择敏感的胸腺细胞没有什么不同，而且胸腺微环境在调节TCR/配体相互作用的结果中发挥了作用。
The specificity of the T cell receptor (TCR) repertoire for foreign peptide bound to self-major histocompatibility complex (MHC) molecules is determined in large part by positive and negative selection processes in the thymus, yet the mechanisms of these selection events remain unknown. Using in vitro organ culture of thymi isolated from mice transgenic for a TCR-alpha/beta specific for cytochrome c peptide bound to I-Ek, we analyzed the developmental timing of negative selection (deletion). On the basis of the experiments described below, we conclude that all CD4+8+ thymocytes, and only CD4+8+ thymocytes, are susceptible to negative selection mediated by the cytochrome c peptide antigen. First, we found that deletion of thymocytes resulting from addition of the cytochrome c peptide to the thymic organ cultures can occur at the earliest stage of TCR, CD4, and CD8 coexpression. Second, we found that CD4+8+ thymocytes isolated from positively selecting or nonselecting MHC haplotypes were equally efficiently deleted in vitro, suggesting that positive selection is not a prerequisite for deletion. Third, we examined the effects of TCR/ligand avidity on the developmental timing of deletion by varying the concentration of cytochrome c peptide added to the organ cultures. We detected deletion only at the CD4+8+ stage: intermediate concentrations of peptide that resulted in partial deletion of CD4+8+ cells did not eliminate the appearance of mature CD4+8- cells. Finally, we found that CD4+8- thymocytes were resistant to deletion as well as activation by peptide antigen added to the intact organ cultures. Nevertheless, the CD4+8- thymocytes isolated from the peptide-treated organ cultures responded vigorously to peptide presented by spleen cells in vitro. Thus, the T cells were tolerant of (but not anergized by) self-antigen encountered in thymic organ culture. Together, these results indicate that thymocytes susceptible to negative selection are not developmentally distinct from those susceptible to positive selection, and further, that the thymic microenvironment plays a role in regulating the outcome of TCR/ligand interactions.