title: Crystal structures of murine MHC Class I H-2 D(b) and K(b) molecules in complex with CTL epitopes from influenza A virus: implications for TCR repertoire selection and immunodominance.
abstract: Cytotoxic T lymphocyte (CTL) responses against influenza A virus in C57BL/6 mice are dominated by a small number of viral peptides among many that are capable of binding to major histocompatibility complex (MHC) class I molecules. The basis of this limited immune recognition is unknown. Here, we present X-ray structures of MHC class I molecules in complex with two immunodominant epitopes (PA(224-233)/D(b) and PB1(703-711)/K(b)) and one non-immunogenic epitope (HA(468-477)/D(b)) of the influenza A virus. The immunodominant peptides are each characterized by a bulge at the C terminus, lifting P6 and P7 residues out of the MHC groove, presenting featured structural elements to T-cell receptors (TCRs). Immune recognition of PA(224-233)/D(b) will focus largely on the exposed P7 arginine residue. In contrast, the non-immunogenic HA(468-477) peptide lacks prominent features in this C-terminal bulge. In the K(b)-bound PB1(703-711) epitope, the bulge results from a non-canonical binding motif, such that the mode of presentation of this peptide strongly resembles that of D(b)-bound peptides. Given that PA(224-233)/D(b), PB1(703-711)/K(b) and the previously defined NP(366-374)/D(b) epitopes dominate the primary response to influenza A virus in C57BL/6 mice, our findings indicate that residues of the C-terminal bulge are important in selection of the immunodominant CTL repertoire.
authors.affiliation: Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Meijers
authors.forename: Char-Chang
authors.initials: CC
authors.lastname: Lai
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yang
authors.forename: Jin-Huan
authors.initials: JH
authors.lastname: Liu
authors.forename: Weimin
authors.initials: W
authors.lastname: Zhong
authors.forename: Jia-Huai
authors.initials: JH
authors.lastname: Wang
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D006183:H-2 Antigens / Q000737:chemistry* / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000737:chemistry*; D009980:Influenza A virus / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D013499:Surface Properties; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell