T cell receptor CDR3 loops influence αβ pairing
T cell receptor CDR3 loops influence αβ pairing
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DOI：
10.1016/j.molimm.2010.01.012
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发表时间：
2010-04-01
影响因子：
3.6
通讯作者：
Dyson, Julian
中科院分区：
文献类型：
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作者：
Bartok, Istvan;Holland, Stephen J.;Dyson, Julian
T细胞受体转移是产生靶向感染和恶性肿瘤的抗原特异性T细胞的有吸引力的策略。转导的和内源性TCR链的交叉配对产生新的和潜在的自身反应性特异性并稀释治疗性TCR。这是进一步复杂的，因为每个α β对的配对效率是不可预测的，并且影响它的因素没有很好地表征。互补决定区3（CDR3）环是由于V（D）J连接处的核苷酸插入和缺失导致的TCR α和β多样性的主要来源。考虑到这些非种系编码结构的组成和长度的可变性，在一些TCR异源二聚体形成期间可能发生结构应变，从而导致观察到的配对限制。HY特异性T细胞受体C6的β链就是这样一个例子。尽管与C6 α链有效配对，但与许多其他α链的配对效果较差。为了研究长的C6 β CDR 3区是否是这种效应的基础，将其用短的人工CDR 3区替换，所述短的人工CDR 3区恢复与内源性α链库的有效配对。分子建模与导致空间不相容性的β链CDR 3区一致。尽管配对差和表面表达低，WT C6 β链介导逆转录小鼠中的阳性选择。(C)2010爱思唯尔有限公司版权所有。
T cell receptor transfer is an attractive strategy for the generation of antigen specific T cells to target infection and malignancy. Cross pairing of the transduced and endogenous TCR chains produces new and potentially auto-reactive specificities and dilutes the therapeutic TCR. This is further complicated as the efficiency of pairing for each alpha beta pair is unpredictable and the factors which influence it are not well characterized. Complementarity determining region 3 (CDR3) loops are the main sources of TCR alpha and beta diversity due to nucleotide insertion and deletion at V(D)J junctions. Given the variability in composition and length of these non-germ line encoded structures, it is likely that structural strain may occur during formation of some TCR hetero-dimers contributing to the observed pairing restrictions. The beta chain of the HY specific T cell receptor C6 is such an example. Despite pairing efficiently with the C6 alpha chain, it pairs poorly with many other alpha chains. To investigate whether the long, C6 beta CDR3 region underlies this effect, it was replaced with a short, artificial CDR3 region that restored efficient pairing with the endogenous alpha chain repertoire. Molecular modelling is consistent with the beta chain CDR3 region causing steric incompatibility. Despite poor pairing and low surface expression, the WT C6 beta chain mediates positive selection in retrogenic mice. (C) 2010 Elsevier Ltd. All rights reserved.