Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding
Abstract
TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. In conclusion, the isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy.
- Authors:
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1563054
- Alternate Identifier(s):
- OSTI ID: 1471537
- Grant/Contract Number:
- AC02-76SF00515; 5 T32 AI07290; F31 CA216926-01; U19 AI57229; R01 AI103867; R01AI096879; R01 NS071518; PO1 A1091580; NCI 1U54 CA199090-01; GRFP; EFRI-ODISSEI 1332411; WT101609MA; P41GM103393; 331 ACI-1548562
- Resource Type:
- Published Article
- Journal Name:
- Cell
- Additional Journal Information:
- Journal Name: Cell Journal Volume: 174 Journal Issue: 3; Journal ID: ISSN 0092-8674
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; TCR; MHC; ligand discrimination; catch bond; signaling; structure; CD45; molecular dynamics
Citation Formats
Sibener, Leah V., Fernandes, Ricardo A., Kolawole, Elizabeth M., Carbone, Catherine B., Liu, Fan, McAffee, Darren, Birnbaum, Michael E., Yang, Xinbo, Su, Laura F., Yu, Wong, Dong, Shen, Gee, Marvin H., Jude, Kevin M., Davis, Mark M., Groves, Jay T., Goddard, III, William A., Heath, James R., Evavold, Brian D., Vale, Ronald D., and Garcia, K. Christopher. Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding. United States: N. p., 2018.
Web. doi:10.1016/j.cell.2018.06.017.
Sibener, Leah V., Fernandes, Ricardo A., Kolawole, Elizabeth M., Carbone, Catherine B., Liu, Fan, McAffee, Darren, Birnbaum, Michael E., Yang, Xinbo, Su, Laura F., Yu, Wong, Dong, Shen, Gee, Marvin H., Jude, Kevin M., Davis, Mark M., Groves, Jay T., Goddard, III, William A., Heath, James R., Evavold, Brian D., Vale, Ronald D., & Garcia, K. Christopher. Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding. United States. https://doi.org/10.1016/j.cell.2018.06.017
Sibener, Leah V., Fernandes, Ricardo A., Kolawole, Elizabeth M., Carbone, Catherine B., Liu, Fan, McAffee, Darren, Birnbaum, Michael E., Yang, Xinbo, Su, Laura F., Yu, Wong, Dong, Shen, Gee, Marvin H., Jude, Kevin M., Davis, Mark M., Groves, Jay T., Goddard, III, William A., Heath, James R., Evavold, Brian D., Vale, Ronald D., and Garcia, K. Christopher. Sun .
"Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding". United States. https://doi.org/10.1016/j.cell.2018.06.017.
@article{osti_1563054,
title = {Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding},
author = {Sibener, Leah V. and Fernandes, Ricardo A. and Kolawole, Elizabeth M. and Carbone, Catherine B. and Liu, Fan and McAffee, Darren and Birnbaum, Michael E. and Yang, Xinbo and Su, Laura F. and Yu, Wong and Dong, Shen and Gee, Marvin H. and Jude, Kevin M. and Davis, Mark M. and Groves, Jay T. and Goddard, III, William A. and Heath, James R. and Evavold, Brian D. and Vale, Ronald D. and Garcia, K. Christopher},
abstractNote = {TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. In conclusion, the isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy.},
doi = {10.1016/j.cell.2018.06.017},
journal = {Cell},
number = 3,
volume = 174,
place = {United States},
year = {Sun Jul 01 00:00:00 EDT 2018},
month = {Sun Jul 01 00:00:00 EDT 2018}
}
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https://doi.org/10.1016/j.cell.2018.06.017
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Works referenced in this record:
X-Ray Diffraction data from TCR55 in complex with Pep20/HLA-B35, source of 6BJ8 structure
dataset, January 2019
- Yang, Xinbo
- SBGrid Data Bank
X-Ray Diffraction data from TCR589 in complex with HIV(Pol448-456)/HLA-B35, source of 6BJ2 structure
dataset, January 2019
- Jude, Kevi M.
- SBGrid Data Bank
Works referencing / citing this record:
Membrane Organization and Physical Regulation of Lymphocyte Antigen Receptors: A Biophysicist’s Perspective
journal, July 2019
- Limozin, Laurent; Puech, Pierre-Henri
- The Journal of Membrane Biology, Vol. 252, Issue 4-5
Molecular evolution of peptides by yeast surface display technology
journal, January 2019
- Linciano, Sara; Pluda, Stefano; Bacchin, Arianna
- MedChemComm, Vol. 10, Issue 9
A cell topography-based mechanism for ligand discrimination by the T cell receptor
journal, June 2019
- Fernandes, Ricardo A.; Ganzinger, Kristina A.; Tzou, Justin C.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 28
X-Ray Diffraction data from TCR55 in complex with Pep20/HLA-B35, source of 6BJ8 structure
dataset, January 2019
- Yang, Xinbo
- SBGrid Data Bank
X-Ray Diffraction data from TCR589 in complex with HIV(Pol448-456)/HLA-B35, source of 6BJ2 structure
dataset, January 2019
- Jude, Kevi M.
- SBGrid Data Bank
X-Ray Diffraction data from TCR55 in complex with HIV(Pol448-456)/HLA-B35, source of 6BJ3 structure
dataset, January 2019
- Jude, Kevin M.
- SBGrid Data Bank
Membrane Organization and Physical Regulation of Lymphocyte Antigen Receptors: A Biophysicist’s Perspective
journal, July 2019
- Limozin, Laurent; Puech, Pierre-Henri
- The Journal of Membrane Biology, Vol. 252, Issue 4-5
Molecular evolution of peptides by yeast surface display technology
journal, January 2019
- Linciano, Sara; Pluda, Stefano; Bacchin, Arianna
- MedChemComm, Vol. 10, Issue 9
A cell topography-based mechanism for ligand discrimination by the T cell receptor
journal, June 2019
- Fernandes, Ricardo A.; Ganzinger, Kristina A.; Tzou, Justin C.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 28
G‐Protein‐Coupled Receptor–Membrane Interactions Depend on the Receptor Activation State
journal, October 2019
- Bhattarai, Apurba; Wang, Jinan; Miao, Yinglong
- Journal of Computational Chemistry, Vol. 41, Issue 5
NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology
journal, February 2019
- Mallis, Robert J.; Brazin, Kristine N.; Duke-Cohan, Jonathan S.
- Journal of Biomolecular NMR, Vol. 73, Issue 6-7
Tensile and compressive force regulation on cell mechanosensing
journal, May 2019
- Chen, Yunfeng; Li, Zhiyong; Ju, Lining Arnold
- Biophysical Reviews, Vol. 11, Issue 3
T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide–MHC complexes
journal, November 2018
- Bentzen, Amalie K.; Such, Lina; Jensen, Kamilla K.
- Nature Biotechnology, Vol. 36, Issue 12
TCR–pMHC bond conformation controls TCR ligand discrimination
journal, September 2019
- Sasmal, Dibyendu K.; Feng, Wei; Roy, Sobhan
- Cellular & Molecular Immunology, Vol. 17, Issue 3
Checkpoint blockade and nanosonosensitizer-augmented noninvasive sonodynamic therapy combination reduces tumour growth and metastases in mice
journal, May 2019
- Yue, Wenwen; Chen, Liang; Yu, Luodan
- Nature Communications, Vol. 10, Issue 1
In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
journal, November 2019
- Jiang, Wei; Birtley, James R.; Hung, Shu-Chen
- Nature Communications, Vol. 10, Issue 1
CD8 helps TCR catch slippery self pMHC
journal, November 2018
- Dushek, Omer; Dustin, Michael L.
- Nature Immunology, Vol. 19, Issue 12
Mechanosensing through immunoreceptors
journal, September 2019
- Zhu, Cheng; Chen, Wei; Lou, Jizhong
- Nature Immunology, Vol. 20, Issue 10
TCR–pMHC kinetics under force in a cell-free system show no intrinsic catch bond, but a minimal encounter duration before binding
journal, July 2019
- Limozin, Laurent; Bridge, Marcus; Bongrand, Pierre
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 34
How drag sharpens a T cell’s view on antigen
journal, August 2019
- Schütz, Gerhard J.; Huppa, Johannes B.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 34
Human cytomegalovirus-specific T-cell receptor engineered for high affinity and soluble expression using mammalian cell display
journal, February 2019
- Wagner, Ellen K.; Qerqez, Ahlam N.; Stevens, Christopher A.
- Journal of Biological Chemistry, Vol. 294, Issue 15
A molecular switch in mouse CD1d modulates natural killer T cell activation by α-galactosylsphingamides
journal, August 2019
- Wang, Jing; Guillaume, Joren; Janssens, Jonas
- Journal of Biological Chemistry, Vol. 294, Issue 39
Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies
journal, February 2019
- Trinklein, Nathan D.; Pham, Duy; Schellenberger, Ute
- mAbs, Vol. 11, Issue 4
The TCR is an allosterically regulated macromolecular machinery changing its conformation while working
journal, August 2019
- Schamel, Wolfgang W.; Alarcon, Balbino; Minguet, Susana
- Immunological Reviews, Vol. 291, Issue 1
CD45 functions as a signaling gatekeeper in T cells
journal, October 2019
- Courtney, Adam H.; Shvets, Alexey A.; Lu, Wen
- Science Signaling, Vol. 12, Issue 604
Membrane Ultrastructure and T Cell Activation
journal, September 2018
- Pettmann, Johannes; Santos, Ana Mafalda; Dushek, Omer
- Frontiers in Immunology, Vol. 9
2D Kinetic Analysis of TCR and CD8 Coreceptor for LCMV GP33 Epitopes
journal, October 2018
- Kolawole, Elizabeth M.; Andargachew, Rakieb; Liu, Baoyu
- Frontiers in Immunology, Vol. 9
Integrating Experiment and Theory to Understand TCR-pMHC Dynamics
journal, December 2018
- Buckle, Ashley M.; Borg, Natalie A.
- Frontiers in Immunology, Vol. 9