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

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 3rd; James R Heath; Brian D Evavold; Ronald D Vale; K Christopher Garcia

doi:10.1016/j.cell.2018.06.017

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

Cell. 2018 Jul 26;174(3):672-687.e27. doi: 10.1016/j.cell.2018.06.017.

Authors

Leah V Sibener¹, Ricardo A Fernandes², Elizabeth M Kolawole³, Catherine B Carbone⁴, Fan Liu⁵, Darren McAffee⁶, Michael E Birnbaum¹, Xinbo Yang², Laura F Su⁷, Wong Yu⁷, Shen Dong², Marvin H Gee¹, Kevin M Jude², Mark M Davis⁸, Jay T Groves⁶, William A Goddard 3rd⁹, James R Heath¹⁰, Brian D Evavold³, Ronald D Vale¹¹, K Christopher Garcia¹²

Affiliations

¹ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
⁴ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA; Institute for Systems Biology, Seattle, WA 98109, USA.
⁶ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
⁷ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁰ Institute for Systems Biology, Seattle, WA 98109, USA.
¹¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.

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.

Keywords: CD45; MHC; TCR; catch bond; ligand discrimination; molecular dynamics; signaling; structure.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Female
Histocompatibility Antigens Class I / physiology*
Humans
Kinetics
Ligands
Lymphocyte Activation / physiology*
Major Histocompatibility Complex / physiology
Male
Middle Aged
Molecular Dynamics Simulation
Oligopeptides
Peptides
Protein Binding / physiology
Receptors, Antigen, T-Cell / metabolism
Receptors, Antigen, T-Cell / physiology
Signal Transduction
Single Molecule Imaging
T-Lymphocytes / physiology

Substances

Histocompatibility Antigens Class I
Ligands
MHC binding peptide
Oligopeptides
Peptides
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding