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Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding

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, William A., III and Heath, James R. and Evavold, Brian D. and Vale, Ronald D. and Garcia, K. Christopher (2018) Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding. Cell, 174 (3). pp. 672-687. ISSN 0092-8674. PMCID PMC6140336.

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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. 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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Goddard, William A., III0000-0003-0097-5716
Heath, James R.0000-0001-5356-4385
Garcia, K. Christopher0000-0001-9273-0278
Alternate Title:Isolation and visualization of a structural trigger that uncouples TCR signaling from pMHC binding
Additional Information:© 2018 Elsevier Inc. Received 10 November 2017, Revised 13 March 2018, Accepted 7 June 2018, Available online 26 July 2018. We thank Vince Luca, Mark O’Dair, Christopher Jakobson, Ignacio Moraga, Naresha Saligrama, and Masafumi Takaguchi for helpful discussions or reagents. This study was supported by the NIH (5 T32 AI07290 to L.V.S., F31 CA216926-01 to M.H.G., U19 AI57229 to K.C.G. and M.M.D., R01 AI103867 to K.C.G., R01AI096879 and R01 NS071518 to B.D.E., PO1 A1091580 to J.T.G., and NCI 1U54 CA199090-01 to J.R.H.), HHMI (K.C.G., M.M.D., and R.D.V.), NSF (GRFP to L.V.S. and EFRI-ODISSEI 1332411 to W.A.G.), Wellcome Trust (WT101609MA to R.A.F.), Parker Institute for Cancer Immunotherapy and Jean Perkins Foundation (J.R.H.). The Berkeley Center for Structural Biology is supported by the NIH, NIGMS, and HHMI. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract DE-AC02-05CH11231. The Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. DOE, Office of Science, Office of Basic Energy Sciences under DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH and NIGMS (including P41GM103393). Extreme Science and Engineering Discovery Environment (XSEDE) is supported by the NSF grant 331 ACI-1548562. Author Contributions: L.V.S. and K.C.G. conceived the project and wrote the manuscript. L.V.S. performed binding and signaling analysis and designed and performed yeast selections. L.V.S., X.Y., and K.M.J. performed crystallization experiments and structure determinations. D.M. performed 2D dwell-time experiments. C.B.C. performed Zap imaging and CD45 exclusion experiments. E.M.K. performed BFP and 2D micropipette measurements. L.F.S. and W.Y. performed the primary cell tetramer staining and clone analysis. R.A.F., M.H.G., and M.E.B. provided technical and scientific insights. F.L. performed the MD simulations. M.E.B., M.M.D., B.D.E., W.A.G., J.T.G., J.R.H., R.D.V., and K.C.G. supervised the research. All authors edited the manuscript. Declaration of Interests: LVS, MHG, and KCG are co-founders of 3T Biosciences.
Funding AgencyGrant Number
NIH Predoctoral Fellowship5 T32 AI07290
NIH Postdoctoral FellowshipF31 CA216926-01
NIHU19 AI57229
NIHR01 AI103867
NIHR01 AI096879
NIHR01 NS071518
NIHPO1 A1091580
NIH1U54 CA199090-01
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
Wellcome TrustWT101609MA
Parker Institute for Cancer ImmunotherapyUNSPECIFIED
Jean Perkins FoundationUNSPECIFIED
Department of Energy (DOE)DE-AC02-05CH11231
Department of Energy (DOE)DE-AC02-76SF00515
Subject Keywords:TCR; MHC; ligand discrimination; catch bond; signaling; structure; CD45; molecular dynamics
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Issue or Number:3
PubMed Central ID:PMC6140336
Record Number:CaltechAUTHORS:20180726-081557948
Persistent URL:
Official Citation:Leah V. Sibener, Ricardo A. Fernandes, Elizabeth M. Kolawole, Catherine B. Carbone, Fan Liu, Darren McAffee, Michael E. Birnbaum, Xinbo Yang, Laura F. Su, Wong Yu, Shen Dong, Marvin H. Gee, Kevin M. Jude, Mark M. Davis, Jay T. Groves, William A. Goddard, James R. Heath, Brian D. Evavold, Ronald D. Vale, K. Christopher Garcia, Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding, Cell, Volume 174, Issue 3, 2018, Pages 672-687.e27, ISSN 0092-8674, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88294
Deposited By: Tony Diaz
Deposited On:26 Jul 2018 15:34
Last Modified:18 Dec 2019 18:36

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