title: Structure of a complex of the human alpha/beta T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity.
abstract: The alpha/beta T cell receptor (TCR) HA1.7 specific for the hemagglutinin (HA) antigen peptide from influenza A virus is HLA-DR1 restricted but cross-reactive for the HA peptide presented by the allo-major histocompatibility complex (MHC) class II molecule HLA-DR4. We report here the structure of the HA1.7/DR4/HA complex, determined by X-ray crystallography at a resolution of 2.4 A. The overall structure of this complex is very similar to the previously reported structure of the HA1.7/DR1/HA complex. Amino acid sequence differences between DR1 and DR4, which are located deep in the peptide binding groove and out of reach for direct contact by the TCR, are able to indirectly influence the antigenicity of the pMHC surface by changing the conformation of HA peptide residues at position P5 and P6. Although TCR HA1.7 is cross-reactive for HA presented by DR1 and DR4 and tolerates these conformational differences, other HA-specific TCRs are sensitive to these changes. We also find a dependence of the width of the MHC class II peptide-binding groove on the sequence of the bound peptide by comparing the HA1.7/DR4/HA complex with the structure of DR4 presenting a collagen peptide. This structural study of TCR cross-reactivity emphasizes how MHC sequence differences can affect TCR binding indirectly by moving peptide atoms.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. jens.hennecke@Micromet.de
authors.forename: Jens
authors.initials: J
authors.lastname: Hennecke
authors.forename: Don C
authors.initials: DC
authors.lastname: Wiley
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D003429:Cross Reactions; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015798:HLA-DR1 Antigen; D015804:HLA-DR4 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D016693:Receptors, Antigen, T-Cell, alpha-beta