title: Minimal conformational plasticity enables TCR cross-reactivity to different MHC class II heterodimers.
abstract: Successful immunity requires that a limited pool of αβ T-cell receptors (TCRs) provide cover for a vast number of potential foreign peptide antigens presented by 'self' major histocompatibility complex (pMHC) molecules. Structures of unligated and ligated MHC class-I-restricted TCRs with different ligands, supplemented with biophysical analyses, have revealed a number of important mechanisms that govern TCR mediated antigen recognition. HA1.7 TCR binding to the influenza hemagglutinin antigen (HA(306-318)) presented by HLA-DR1 or HLA-DR4 represents an ideal system for interrogating pMHC-II antigen recognition. Accordingly, we solved the structure of the unligated HA1.7 TCR and compared it to both complex structures. Despite a relatively rigid binding mode, HA1.7 T-cells could tolerate mutations in key contact residues within the peptide epitope. Thermodynamic analysis revealed that limited plasticity and extreme favorable entropy underpinned the ability of the HA1.7 T-cell clone to cross-react with HA(306-318) presented by multiple MHC-II alleles.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Holland
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.forename: Sabrina
authors.initials: S
authors.lastname: Vollers
authors.forename: J Mauricio
authors.initials: JM
authors.lastname: Calvo-Calle
authors.forename: Florian
authors.initials: F
authors.lastname: Madura
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
authors.forename: Andrew
authors.initials: A
authors.lastname: Godkin
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008213:Lymphocyte Activation; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D015798:HLA-DR1 Antigen; D015804:HLA-DR4 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta