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.

Figure 1.

The structures of TCR HA1.7 bound to HLA-DR1 and HLA-DR4 are very similar. Superposition of the TCR V domains and the MHC class II antigen peptide binding groove of the TCR HA1.7/DR4/HA structure (blue) and the TCR HA1.7/DR1/HA structure (red; reference 4). The figure was created with MOLSCRIPT (reference 75).

Figure 2.

Allelic sequence differences between DR1 and DR4 are not accessible for direct contact by the TCR. (A) Sequence alignment of the DR1 (DRB1*0101) and DR4 (DRB1*0401) β-chains. For DR4 only the 15 residues differences are shown. (B) Allelic differences in the peptide-binding groove of DR1 (top row; reference 4) and DR4 (bottom row). Those residues that are different between DR1 and DR4 and map to the surface of the peptide-binding groove are colored. The HA peptide (yellow) is shown as a stick model in the partial view (left) and as a solvent accessible surface in the view of the whole peptide binding groove (right). Figures were prepared with GRASP (reference 76).

Figure 3.

DR1 and DR4 allelic sequence differences cause conformational differences in the HA peptide structure. Changes around HA peptide residue P6 Thr313 (A) and P5 Asn312 (B) when presented by DR1 (left; reference 4) and DR4 (right). The conformation of the HA antigen peptide (yellow) bound to DR1 and DR4 (gray) depends on polymorphic MHC residues (magenta) and influences recognition by the TCR (green) (Van-der-Waals contacts: dashed black lines; potential hydrogen bonds: dashed red lines). Side views into the peptide binding groove are shown with the HA peptide N- to COOH-terminal direction from right to left in A and left to right in B. To allow a better view into the peptide binding groove, the helix in front (α1 domain α-helix in A and β1 domain α-helix in B), which would otherwise block the view, are rendered transparent. Figures were prepared with MOLSCRIPT (reference 75) and Raster3D (reference 77).

Figure 4.

The sequence of the bound peptide determines the width of the DR4 peptide-binding groove. Differences between the structure of the β1 α-helix from residue 62β to 70β in DR4 presenting the HA peptide (yellow) and presenting the collagen II peptide, Col 1168–1180 (red, reference 35). The structure of DR4/HA was determined in complex with a TCR, while DR4/Col was not. The figure was prepared with MOLSCRIPT (reference 75).