A Structural Basis for Varied αβ TCR Usage against an Immunodominant EBV Antigen Restricted to a HLA-B8 Molecule

Abstract

EBV is a ubiquitous and persistent human pathogen, kept in check by the cytotoxic T cell response. In this study, we investigated how three TCRs, which differ in their T cell immunodominance hierarchies and gene usage, interact with the same EBV determinant (FLRGRAYGL), bound to the same Ag-presenting molecule, HLA-B8. We found that the three TCRs exhibit differing fine specificities for the viral Ag. Further, via structural and biophysical approaches, we demonstrated that the viral Ag provides the greatest energetic contribution to the TCR–peptide-HLA interaction, while focusing on a few adjacent HLA-based interactions to further tune fine-specificity requirements. Thus, the TCR engages the peptide-HLA with the viral Ag as the main glue, such that neighboring TCR–MHC interactions are recruited as a supportive adhesive. Collectively, we provide a portrait of how the host’s adaptive immune response differentially engages a common viral Ag.

Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune Response

“…To assess the effect of each mutation on the pMHC complex stability, a thermal shift assay was performed using fluorescent dye Sypro orange to monitor the protein unfolding as previously described (Gras et al, 2012). Results are reported in Supplemental Table 3.…”

Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope

“…Several structures of public TCRs in complex with pMHC have been reported: TCR JM22 bound to an influenza-derived peptide presented by HLA-A2 (22), TCRs bound to EBV-derived peptides presented by HLA-B8 (23)(24)(25)(26), and TCR RA14 bound to CMV NLV presented by HLA-A2 (27). In some cases these studies have identified unusual structural features of the selecting pMHC ligand, such as limited solvent accessibility or bulging of the viral peptide, which may explain the selection of dominant TCRs (22,23,26), whereas in other cases such features are not evident (24,25,27).…”

Nα-Terminal Acetylation for T Cell Recognition: Molecular Basis of MHC Class I–Restricted Nα-Acetylpeptide Presentation

“…This conformational alteration of Arg 62 also has been observed by others in two HLA-B8 structures (Fig. 5B) (37), one of which bound to a peptide with P1-Gly and its Arg 62 is at position 1, whereas in the other, the P1-Phe sterically forces the Arg 62 away to position 2 where it can engage and trigger various TCRs (38). Taking these previous findings into consideration, we hypothesized that in our structure, the acetyl moiety would provide a similar stereochemical effect as the phenyl group of Phe and that the Arg 62 at position 2 might contact with an incoming TCR.…”