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Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition

Peng Wu,Tongtong Zhang,Baoyu Liu,Panyu Fei,Lei Cui,Rui Qin,Huaying Zhu,Danmei Yao,Ryan J. Martinez,Wei Hu,Chenyi An,Yong Zhang,Junwei Liu,Jiawei Shi,Juan Fan,Weiwei Yin,Jie Sun,Chun Zhou,Xun Zeng,Chenqi Xu,Jianan Wang,Brian D. Evavold,Cheng Zhu,Wei Chen,Jizhong Lou

Summary TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.