Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen
Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen
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DOI：
10.1182/blood-2010-12-326736
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发表时间：
2011-07-14
期刊：
影响因子：
20.3
通讯作者：
Stauss, Hans J.
中科院分区：
文献类型：
--
作者：
Thomas, Sharyn;Xue, Shao-An;Stauss, Hans J.
我们已经测试了保留肽特异性的亲和力成熟的TCR是否提高了原代人CD 8（+）T细胞产生抗原特异性应答的能力。我们发现TCR亲和力与T细胞反应的速度相关。高亲和力TCR-抗原相互作用迅速引发T细胞应答，但低亲和力TCR/抗原相互作用需要更长的时间来引发相同的应答。在“天然”亲和力范围内，增加的TCR-抗原亲和力与T细胞识别低浓度抗原的能力提高相关。然而，与野生型TCR相比，具有700倍增强的对MHC-抗原的亲和力的亲和力成熟TCR需要100倍更高的抗原密度来启动T细胞应答。使用修饰的肽来降低TCR与抗原相互作用的亲和力，我们证明亲和力成熟的TCR没有缺陷，在识别低浓度的修饰的肽方面比野生型TCR上级。这些数据表明，增强TCR亲和力可以加速T细胞活化的速度，并降低识别低密度MHC-肽抗原的能力。我们预测，未来对人类T细胞库的研究将揭示2种类型的低亲和力T细胞：快反应和慢反应，分别具有高亲和力和低亲和力TCR。（Blood.2011;118（2）：319-329）
We have tested whether affinity-matured TCRs that retain peptide specificity improve the ability of primary human CD8(+) T cells to mount antigen-specific responses. We found that TCR affinity correlated with the speed of T-cell responses. High affinity TCR-antigen interactions rapidly initiated T-cell responses, but low affinity TCR/antigen interactions required longer time periods to elicit the same responses. Within the "natural" affinity range, increased TCR-to-antigen affinity correlated with improved ability of T cells to recognize low concentration of antigen. However, affinity-matured TCR with 700-fold enhanced affinity for MHC-to-antigen required 100-fold higher antigen-density to initiate T-cell responses than did wild-type TCR. Using modified peptides to reduce the affinity of TCR-to-antigen interaction, we demonstrate that affinity-matured TCRs are not defective, being superior to wild-type TCR in recognizing low concentration of modified pep-tides. These data indicate that enhancing TCR affinity can accelerate the speed of T-cell activation and reduce the ability to recognize low density of MHC-to-peptide antigen. We predict that future studies of the human T-cell repertoire will reveal 2 types of low avidity T cells: fast and slow responders, with high-affinity and low-affinity TCR, respectively. (Blood.2011;118(2):319-329)