Building on earlier work showing that separating force applied to the TCR-peptide-MHC I complex counterintuitively strengthened interactions for T cell stimulating agonist peptides, Wu et al. explored the detailed dynamic interactions using simulations and biophysical assays. A stronger peptide-TCR interface with agonist peptides allowed separating forces to induce new interactions between MHC and TCR domains, which were further strengthened as the MHCα domain separated from β2-microglobulin. These dynamic changes may help explain the impact of HLA polymorphisms and cancer-associated mutations on TCR antigen recognition.
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.
Author Info: (1) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058,
Author Info: (1) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (2) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (3) Coulter Department of Biomedical Engineering, Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA. (4) School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China. (5) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (6) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (7) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (8) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (9) Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA. (10) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (11) School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China. (12) Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (13) Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China. (14) Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China. (15) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (16) Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China. (17) Department of Cell Biology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (18) School of Public Health and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (19) State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, and First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (20) State Key Laboratory of Molecular Biology, Chinese Academy Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China. (21) Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (22) Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA. (23) Coulter Department of Biomedical Engineering, Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA. (24) Department of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Modern Optical Instrumentation, Zhejiang University, Hangzhou 310058, China. Electronic address: jackweichen@zju.edu.cn. (25) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jlou@ibp.ac.cn.
