Thymic selection stifles TCR reactivity with the main chain structure of MHC and forces interactions with the peptide side chains.
Thymic selection stifles TCR reactivity with the main chain structure of MHC and forces interactions with the peptide side chains.
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DOI：
10.1016/j.molimm.2006.03.025
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发表时间：
2008-02
影响因子：
3.6
通讯作者：
E. Huseby;J. Kappler;P. Marrack
中科院分区：
文献类型：
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作者：
E. Huseby;J. Kappler;P. Marrack
接种胸腺的干细胞既不携带抗原受体，也不携带成熟T细胞所特有的辅助受体，即CD 4或CD 8。进入胸腺后，注定携带由α和β链组成的T细胞受体（TCR）的细胞通过重排多个Vα中的一个与多个J α中的一个相邻，以及多个Vβ中的一个与一个或多个Dβ和多个Jβ中的一个相邻来构建这些链的基因（杰克逊and Krangel，2006）。由于所有这些元件都是由种系编码的，因此可以想象TCR+胸腺细胞可能具有非常大的、但遗传上固定的抗原特异性。然而，核苷酸可以在这些元件之间的连接处被去除或引入，因此这些连接点（N区域）是非常随机的，并且不受遗传控制（Davis和Bjorkman，1988）。N区编码TCRα和β多肽的CDR 3环的一部分，并且CDR 3区是TCR与其配体接触的区域的主要组分（Rudolph等人，2006年）。因此，TCR的生殖系特异性被它们的非生殖系N区修饰，并且胸腺细胞携带在不同程度上表现它们的生殖系编码特异性的TCR。αβ TCR被认为是相当MHC和肽特异性的。并非所有的胸腺细胞都注定要成为成熟的T细胞。在胸腺中的选择测试每个胸腺细胞上TCR的特异性，并基于这些，挑选出允许成熟的细胞。许多实验已经证明，表达对结合宿主主要组织相容性复合体（MHC）蛋白的自身肽具有很少或没有亲和力的TCR的胸腺细胞在此阶段死亡，这是由于未能通过其TCR接收存活信号。发育中的胸腺细胞表达对结合宿主MHC蛋白的自身肽具有相对高亲和力的TCR，其经历负选择并且也死亡，然而这是TCR信号事件。只有表达对与宿主MHC蛋白结合的自身肽具有“中等亲和力”的TCR的胸腺细胞才被发出存活的信号，这一过程称为阳性选择（Goldrath和Bevan，1999; von Boehmer等人，2003年）。然后，这些胸腺细胞可以选择成为CD 4 + T细胞或CD 8 + T细胞。
The stem cells which seed the thymus bear neither receptors for antigen nor the coreceptors which are characteristic of mature T cells, CD4 or CD8. After entering the thymus, cells destined to bear T cell receptors (TCRs) made up of α and β chains, construct the genes for these chains by rearranging one of many Vαs to lie next to one of many Jαs, and one of many Vβs to lie next to one or more version of Dβ and one of a number of Jβs (Jackson and Krangel, 2006). Since all these elements are encoded by the germ line, one might imagine that TCR+ thymocytes might have a very large, but genetically fixed, set of specificities for antigen. However, nucleotides can be removed or introduced at the junctions between these elements, and thus these joining points (N regions) are quite random, and not genetically controlled (Davis and Bjorkman, 1988). N regions code for part of the CDR3 loops of TCRα and β polypeptides and the CDR3 regions are a major component of the area of TCRs which contact their ligands (Rudolph et al., 2006). Consequently the germ line specificities of TCRs are modified by their nongerm line N regions and thymocytes bear TCRs which manifest their germline encoded specificities to varying degrees. αβTCRs are thought to be quite MHC and peptide specificNot all thymocytes are destined to become mature T cells. Selection in the thymus tests the specificities of the TCRs on each thymocyte and, based on these, picks out which cells are allowed to mature. Many experiments have demonstrated that thymocytes expressing TCRs with little or no affinity for self peptides bound to host Major Histocompatibility Complex (MHC) proteins die at this stage due to the failure to receive a survival signal through their TCR. Developing thymocytes expressing a TCR with a relatively high affinity for self peptides bound to host MHC proteins undergo negative selection and also die, however this is a TCR signaled event. Only thymocytes which express a TCR with a “moderate affinity” for self peptides bound to host MHC proteins are signaled to live, a process called positive selection (Goldrath and Bevan, 1999; von Boehmer et al., 2003). These thymocytes, then have the choice to become either a CD4+ T cell or a CD8+ T cell.