Crystal structures of murine MHC class IH-2 Db and Kb molecules in complex with CTL Epitopes from influenza A virus:: Implications for TCR repertoire selection and immunodominance

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 (TCR-s). 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 NP366-374/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. (C) 2004 Elsevier Ltd. All rights reserved.