On Jan. 31，Molecular Cell published online the latest research "Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition" from Prof. Wei Chen’s group in the Research Center of Molecular Medicine, Zhejiang University. The study revealed that mechanical force-induced pMHC-I conformational changes determine the successful recognition of foreign antigen and tumor antigen (neoantigen) by CD8+ T cell surface receptors (TCRs).
αβ TCRs on T cells recognize peptide-loaded major histocompatibility complexes (pMHCs) on antigen-presenting cells (APCs) 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. This work 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. Under force, mechanical pulling on TCR-pMHC-I complex can induce rotational conformational changes of α1-α2 domains in MHC-I by disrupting the intramolecular interactions between β2 microglobulin and α3 or α1-α2 domains. This rotation enhances TCR-pMHC-I binding by forming new hydrogen bonds within the interface between TCR and pMHC-I. 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. These findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCRpMHC catch bonds but also have implications for T cell-based immunotherapy.
Ph.D. students Peng Wu and Tongtong Zhang from the Research Center of Molecular Medicine, Zhejiang University, Dr. Baoyu Liu from University of Utah School of Medicine, Ph.D. students Panyu Fei from the School of Mechanical Engineering, Zhejiang University and Dr. Lei Cui from Chinese Academy of Sciences are the first authors of this study. Other co-authors include 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. This is a collaborative research with Dr. Jingzhong Lou’s group from the Institute of Biophysics, Chinese Academy of Sciences. The corresponding authors of this article is Prof. Wei Chen and Dr. Jizhong Lou. This work was supported by grants from the National Basic Research Program of China, the National Science Foundation of China, Fundamental Research Funds for the Central Universities.
.
Link of the paper：https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)31072-4
Link of Prof. Wei Chen’s group: https://person.zju.edu.cn/jackweichen
Link of Prof. Jizhong Lou’s group: http://www.ibp.cas.cn/ktzz/ktzz_L/201308/t20130828_3919975.html
