Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding
- Creators
- 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.
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Goddard, William A., III
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Heath, James R.
- Evavold, Brian D.
- Vale, Ronald D.
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Garcia, K. Christopher
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. 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.
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.Attached Files
Accepted Version - nihms-1504900.pdf
Supplemental Material - 1-s2.0-S0092867418307852-mmc1.pdf
Supplemental Material - 1-s2.0-S0092867418307852-mmc2.xlsx
Files
Additional details
- Alternative title
- Isolation and visualization of a structural trigger that uncouples TCR signaling from pMHC binding
- PMCID
- PMC6140336
- Eprint ID
- 88294
- DOI
- 10.1016/j.cell.2018.06.017
- Resolver ID
- CaltechAUTHORS:20180726-081557948
- 5 T32 AI07290
- NIH Predoctoral Fellowship
- F31 CA216926-01
- NIH Postdoctoral Fellowship
- U19 AI57229
- NIH
- R01 AI103867
- NIH
- R01 AI096879
- NIH
- R01 NS071518
- NIH
- PO1 A1091580
- NIH
- 1U54 CA199090-01
- NIH
- Howard Hughes Medical Institute (HHMI)
- NSF Graduate Research Fellowship
- EFRI-1332411
- NSF
- WT101609MA
- Wellcome Trust
- Parker Institute for Cancer Immunotherapy
- Jean Perkins Foundation
- DE-AC02-05CH11231
- Department of Energy (DOE)
- DE-AC02-76SF00515
- Department of Energy (DOE)
- P41GM103393
- NIH
- ACI-1548562
- NSF
- Created
-
2018-07-26Created from EPrint's datestamp field
- Updated
-
2022-03-09Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1289