Structure of a Complex of the Human α/β T Cell Receptor (TCR) HA1.7, Influenza Hemagglutinin Peptide, and Major Histocompatibility Complex Class II Molecule, HLA-DR4 (DRA0101 and DRB10401)

Abstract

The α/β 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 Å. 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.

A Comparative Analysis of the Peptide Repertoires of HLA–DR Molecules Differentially Associated With Rheumatoid Arthritis

“…The binding assay demonstrated that this peptide was good at binding to DR1 and DR2a, but not to DR4, DR10, and DR2b. The core for DR2a was IVIALAGNK, which lacks Leu 4 and Lys 8 .…”

How an alloreactive T-cell receptor achieves peptide and MHC specificity

“…Several studies have examined the structural features of allogeneic TCR-pMHC complexes (8)(9)(10)(11)). An overall assessment of these structures is that rather than demonstrating features that are clearly characteristic of alloreactivity, they illustrate features similar to traditional syngeneic complexes of TCRs with peptides presented by self-MHC (3,12,13).…”

Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes

“…Recombinant α-gliadin/DQ8 protein containing the deamidated peptide sequence QQYPSGEGSFQPSQENPQ was expressed in S2 Drosophila cells and purified as previously described (55). TATD (1,3,6,8-tetraaza-tricyclo[4.4.1.13,8]dodecane) Seattle, Washington, USA) or from published literature (clones 13, 22, and 38, which are DQ8 restricted; clone 233, which is DQ2 restricted; and C7CH17, which is DR4 restricted) (31,32,34,56). Supplemental Table 9 lists each TCR transductant, its corresponding peptide, and its MHC class II restriction.…”