title: T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex.
abstract: T cell receptor (TCR) engagement of peptide-major histocompatibility complex (pMHC) is essential to adaptive immunity, but it is unknown whether TCR signaling responses are influenced by the binding topology of the TCR-peptide-MHC complex. We developed yeast-displayed pMHC libraries that enabled us to identify new peptide sequences reactive with a single TCR. Structural analysis showed that four peptides bound to the TCR with distinct 3D and 2D affinities using entirely different binding chemistries. Three of the peptides that shared a common docking mode, where key TCR-MHC germline interactions are preserved, induced TCR signaling. The fourth peptide failed to induce signaling and was recognized in a substantially different TCR-MHC binding mode that apparently exceeded geometric tolerances compatible with signaling. We suggest that the stereotypical TCR-MHC docking paradigm evolved from productive signaling geometries and that TCR signaling can be modulated by peptides that are recognized in alternative TCR-pMHC binding orientations.
authors.affiliation: Howard Hughes Medical Institute, and Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jarrett J
authors.initials: JJ
authors.lastname: Adams
authors.forename: Samanthi
authors.initials: S
authors.lastname: Narayanan
authors.forename: Baoyu
authors.initials: B
authors.lastname: Liu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Birnbaum
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bowerman
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Aron M
authors.initials: AM
authors.lastname: Levin
authors.forename: Janet M
authors.initials: JM
authors.lastname: Connolly
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015203:Reproducibility of Results; D016415:Sequence Alignment; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D019151:Peptide Library; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
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