title: T-cell receptor (TCR)-peptide specificity overrides affinity-enhancing TCR-major histocompatibility complex interactions.
abstract: αβ T-cell receptors (TCRs) engage antigens using complementarity-determining region (CDR) loops that are either germ line-encoded (CDR1 and CDR2) or somatically rearranged (CDR3). TCR ligands compose a presentation platform (major histocompatibility complex (MHC)) and a variable antigenic component consisting of a short "foreign" peptide. The sequence of events when the TCR engages its peptide-MHC (pMHC) ligand remains unclear. Some studies suggest that the germ line elements of the TCR engage the MHC prior to peptide scanning, but this order of binding is difficult to reconcile with some TCR-pMHC structures. Here, we used TCRs that exhibited enhanced pMHC binding as a result of mutations in either CDR2 and/or CDR3 loops, that bound to the MHC or peptide, respectively, to dissect the roles of these loops in stabilizing TCR-pMHC interactions. Our data show that TCR-peptide interactions play a strongly dominant energetic role providing a binding mode that is both temporally and energetically complementary with a system requiring positive selection by self-pMHC in the thymus and rapid recognition of non-self-pMHC in the periphery.
authors.affiliation: From Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Kim M
authors.initials: KM
authors.lastname: Miles
authors.forename: Florian
authors.initials: F
authors.lastname: Madura
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Holland
authors.forename: Andrea J A
authors.initials: AJ
authors.lastname: Schauenburg
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Godkin
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bulek
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.forename: Hephzibah J E
authors.initials: HJ
authors.lastname: Akpovwa
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Pymm
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Liddy
authors.forename: Malkit
authors.initials: M
authors.lastname: Sami
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity
chemical_list: D022801:Complementarity Determining Regions; D006680:HLA Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008024:Ligands; C408902:MHC binding peptide; D009842:Oligopeptides; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
keywords: Immunology; Major Histocompatibility Complex (MHC); Protein-Protein Interactions; Receptor Structure-Function; T-cell Biology; T-cell Receptor