ArticleMolecular cell2019
Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.
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Article in Molecular cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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99 citing papers in PubMed, 160 citations in OpenAlex.
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- Evaluating the effects of CD8/CD4 on T cell function in terms of TCR-pMHC-coreceptor catch and slip bonds.Frontiers in immunology · 2026Article
- Structure guided analysis of KRAS G12 mutants in HLA-A*11:01 reveals a length encoded immunogenic advantage in G12D.Communications biology · 2025Article
- Evaluating the effects of CD8/CD4 on T cell function in terms of TCR-pMHC-coreceptor catch and slip bonds.bioRxiv : the preprint server for biology · 2025Article
- Atomistic TCR-ligand interactions instruct memory T-cell differentiation.bioRxiv : the preprint server for biology · 2025Article
- Dissection of the trans-endocytosis and signal inhibition functions of CTLA-4 through the study of a disease-associated Y139C mutation.Cellular & molecular immunology · 2025Article
- Three-dimensional traction technology and its application in mechanomedicine.Mechanobiology in medicine · 2025Review
39 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 7 institutions in 2 countries.
Peng WuDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Tongtong ZhangDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Baoyu LiuCoulter 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.
Panyu FeiSchool of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China.
Lei CuiNational 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.
Rui QinDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Huaying ZhuDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Danmei YaoDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Ryan J MartinezDepartment of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Wei HuDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Chenyi AnSchool of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China.
Yong ZhangKey Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Junwei LiuKey Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China.
Jiawei ShiKey Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China.
Juan FanDepartment of Neurobiology, Institute of Neuroscience, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Weiwei YinKey Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China.
Jie SunDepartment of Cell Biology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Chun ZhouSchool of Public Health and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Xun ZengState 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.
Chenqi XuState 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.
Jianan WangDepartment of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Brian D EvavoldDepartment of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Cheng ZhuCoulter Department of Biomedical Engineering, Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Wei ChenDepartment 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.
Jizhong LouNational 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.
Second Affiliated Hospital of Zhejiang University · CNZhejiang University · CNChinese Academy of Sciences · CNEmory University · USFirst Affiliated Hospital Zhejiang University · CNGeorgia Institute of Technology · USSir Run Run Shaw Hospital · CN
Funding
MEDICAL SCIENTIST TRAINING PROGRAMT32GM008169 · NIGMS · EMORY UNIVERSITY · PI GROSS, ROBERT E · 1987 to 2021
$20.3MMechanisms of impaired T-cell mechanosensing of melanoma antigensU01CA214354 · NCI · GEORGIA INSTITUTE OF TECHNOLOGY · PI KROGSGAARD, MICHELLE, ZHU, CHENG · 2017 to 2021
$3.9MSingle-platelet analysis of mechano-reception by GPIb alphaR01HL132019 · NHLBI · GEORGIA INSTITUTE OF TECHNOLOGY · PI ZHU, CHENG · 2016 to 2024
$3.8MExploiting the Mechanobiology of PD-1 for Cancer ImmunotherapyU01CA250040 · NCI · GEORGIA INSTITUTE OF TECHNOLOGY · PI ZHU, CHENG · 2020 to 2024
$3.5MT cell compartmentalization and antiviral responseR01AI124680 · NIAID · EMORY UNIVERSITY · PI GRAKOUI, ARASH, ZHU, CHENG · 2016 to 2020
$3.2MEvolution of CD8+ TCR affinity during chronic viral infectionR01AI096879 · NIAID · EMORY UNIVERSITY · PI EVAVOLD, BRIAN D · 2012 to 2016
$2.1MMechanisms of initiation of T-cell signaling by the TCR-CD3 complexR01GM124489 · NIGMS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI KROGSGAARD, MICHELLE · 2018 to 2021
$2.1MNCI NIH HHS U01 CA214354NCI NIH HHS U01 CA250040NHLBI NIH HHS R01 HL132019NIAID NIH HHS R01 AI096879NIAID NIH HHS R01 AI124680NIGMS NIH HHS R01 GM124489NIGMS NIH HHS T32 GM008169
Abstract
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.
Indexed as
Adaptive ImmunityMechanotransduction, CellularAnimalsHEK293 CellsHLA-A2 AntigenHumansHybridomasMice, Inbred C57BLMice, TransgenicMolecular Dynamics SimulationMutationProtein BindingProtein ConformationReceptors, Antigen, T-CellSingle Molecule ImagingStructure-Activity RelationshipHLA-A2 AntigenReceptors, Antigen, T-Cellantigen recognitioncatch bondsconformational changeimmunotherapymechano-regulationmolecular dynamics simulationspMHCsingle molecule biophysicsTCRTCR triggering
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