Force-Regulated In Situ TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells.
Force-Regulated In Situ TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells.
复制标题
DOI：
10.4049/jimmunol.1501407
复制
发表时间：
2015-10-15
期刊：
影响因子：
--
通讯作者：
Zhu C
中科院分区：
文献类型：
--
作者：
Hong J;Persaud SP;Horvath S;Allen PM;Evavold BD;Zhu C
我们最近发现，TCR-pMHC-I相互作用的二维（2D）和力调节动力学预测CD 8 + T细胞的反应。为了测试这些发现是否适用于CD 4 + T细胞，我们分析了原位3.L2 TCR-pMHC-II相互作用的一个很好的特征面板上的T细胞表面的改变肽配体使用粘附频率测定与微量移液管和热波动和力钳测定与生物膜力探针。我们发现2D有效TCR-pMHC-II亲和力和解离速率与三维（3D）中的表面等离子体共振的相应测量相关，但比其更好地预测T细胞应答。CD 4对MHCII的2D亲和力非常低，接近检测限，使其比CD 8对MHC-I的亲和力低1-2个数量级。此外，在CD 4中没有观察到先前在CD 8中观察到的TCR与pMHC结合的共受体之间的信号依赖性合作。有趣的是，力引起TCR-pMHC-II的捕捉-滑动键的激动剂，但只滑动键的拮抗剂，从而放大了APLs之间的歧视的权力。这些结果表明，3.L2 TCR对pMHC-II的力调节的2D结合动力学决定了CD 4 + T细胞的功能。
We have recently shown that two-dimensional (2D) and force-regulated kinetics of TCR–pMHC-I interactions predict responses of CD8+ T cells. To test whether these findings are applicable to CD4+ T cells, we analyzed the in situ 3.L2 TCR–pMHC-II interactions for a well-characterized panel of altered peptide ligands on the T-cell surface using the adhesion frequency assay with a micropipette and the thermal fluctuation and force-clamp assays with a biomembrane force probe. We found that the 2D effective TCR–pMHC-II affinity and off-rate correlate with, but better predict the T-cell response than, the corresponding measurements with the surface plasmon resonance in three dimensions (3D). The 2D affinity of the CD4 for MHCII was very low, approaching the detection limit, making it 1-2 orders of magnitude lower than the affinity of CD8 for MHC-I. In addition, the signal-dependent cooperation between TCR and co-receptor for pMHC binding previously observed for CD8 was not observed for CD4. Interestingly, force elicited TCR–pMHC-II catch-slip bonds for agonists but slip-only bonds for antagonists, thereby amplifying the power of discrimination between APLs. These results show that the force-regulated 2D binding kinetics of the 3.L2 TCR for pMHC-II determine functions of CD4+ T cells.