title: Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity.
abstract: The T cell antigen receptor (TCR)-peptide-major histocompatibility complex (MHC) interface is composed of conserved and diverse regions, yet the relative contribution of each in shaping recognition by T cells remains unclear. Here we isolated cross-reactive peptides with limited homology, which allowed us to compare the structural properties of nine peptides for a single TCR-MHC pair. The TCR's cross-reactivity was rooted in highly similar recognition of an apical 'hot-spot' position in the peptide with tolerance of sequence variation at ancillary positions. Furthermore, we found a striking structural convergence onto a germline-mediated interaction between the TCR CDR1α region and the MHC α2 helix in twelve TCR-peptide-MHC complexes. Our studies suggest that TCR-MHC germline-mediated constraints, together with a focus on a small peptide hot spot, might place limits on peptide antigen cross-reactivity.
authors.affiliation: Howard Hughes Medical Institute, and Departments of Molecular and Cellular Physiology, and Structural Biology, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.|Banting and Best Department of Medical Research and Department of Molecular Genetics, University of Toronto, Terrence Donnelly Centre for Cellular &Biomolecular Research, Toronto, Ontario, Canada.
authors.forename: Jarrett J
authors.initials: JJ
authors.lastname: Adams
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Samanthi
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Howard Hughes Medical Institute, and Departments of Molecular and Cellular Physiology, and Structural Biology, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Birnbaum
authors.affiliation: Banting and Best Department of Medical Research and Department of Molecular Genetics, University of Toronto, Terrence Donnelly Centre for Cellular &Biomolecular Research, Toronto, Ontario, Canada.
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.affiliation: Department of Chemistry &Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Sydney J
authors.initials: SJ
authors.lastname: Blevins
authors.affiliation: Howard Hughes Medical Institute, and Departments of Molecular and Cellular Physiology, and Structural Biology, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Marvin H
authors.initials: MH
authors.lastname: Gee
authors.affiliation: Howard Hughes Medical Institute, and Departments of Molecular and Cellular Physiology, and Structural Biology, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Leah V
authors.initials: LV
authors.lastname: Sibener
authors.affiliation: Department of Chemistry &Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.affiliation: Howard Hughes Medical Institute, and Departments of Molecular and Cellular Physiology, and Structural Biology, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology*; D018360:Crystallography, X-Ray; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology*
chemical_list: D000941:Antigens; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta