Fast on-rates allow short dwell time ligands to activate T cells
Fast on-rates allow short dwell time ligands to activate T cells
复制标题
DOI：
10.1073/pnas.1000966107
复制
发表时间：
2010-05-11
影响因子：
11.1
通讯作者：
Husebyb, Eric S.
中科院分区：
文献类型：
--
作者：
Govern, Christopher C.;Paczosa, Michelle K.;Husebyb, Eric S.
已经出现了两种截然不同的理论，试图描述 T 细胞配体的效力，一种基于相互作用的 t(1/2)，另一种基于平衡亲和力 (K(D))。在此，我们鉴定并研究了一系列广泛的 T 细胞受体 (TCR)-肽-MHC (pMHC) 相互作用，用于 CD4(+) 细胞，这些细胞具有不同的 K(D) 和结合动力学。我们的数据表明，短 t(1/2) 的配体如果具有快速的结合速率，则可以具有高度刺激性。简单模型表明，这些快速动力学配体具有刺激作用，因为 pMHC 多次结合并重新结合相同的 TCR。当 TCR-pMHC 结合速率超过 TCR-pMHC 在细胞膜内的扩散时，就会发生重新结合，从而产生聚合 t(1/2) (t(a))，该聚合可能比单次 TCR-pMHC 相遇要长得多。考虑到 ta，当配体具有较快的结合速率 (k(on)) 时，配体效能是基于 K(D) 的；而当配体具有较慢的 k(on) 时，配体效能是基于 t(1/2) 的。因此，TCR-pMHC k(on) 允许高亲和力短 t(1/2) 配体遵循动力学校对模型。
Two contrasting theories have emerged that attempt to describe T-cell ligand potency, one based on the t(1/2) of the interaction and the other based on the equilibrium affinity (K(D)). Here, we have identified and studied an extensive set of T-cell receptor (TCR)-peptide- MHC (pMHC) interactions for CD4(+) cells that have differential K(D)s and kinetics of binding. Our data indicate that ligands with a short t(1/2) can be highly stimulatory if they have fast on-rates. Simple models suggest these fast kinetic ligands are stimulatory because the pMHCs bind and rebind the same TCR several times. Rebinding occurs when the TCR-pMHC on-rate outcompetes TCR-pMHC diffusion within the cell membrane, creating an aggregate t(1/2) (t(a)) that can be significantly longer than a single TCR-pMHC encounter. Accounting for ta, ligand potency is K(D)-based when ligands have fast on-rates (k(on)) and t(1/2)-dependent when they have slow k(on). Thus, TCR-pMHC k(on) allow high-affinity short t(1/2) ligands to follow a kinetic proofreading model.