A Shared TCR Bias toward an Immunogenic EBV Epitope Dominates in HLA-B*07:02-Expressing Individuals

EBV is one of the most common viruses found in humans and is prototypic of a persistent viral infection characterized by periods of latency. Across many HLA class I molecules, the latent-specific CD8⁺ T cell response is focused on epitopes derived from the EBNA-3 protein family. In the case of HLA-B*07:02 restriction, a highly frequent class I allele, the T cell response is dominated by an epitope spanning residues 379-387 of EBNA-3 (RPPIFIRRL [EBV_RPP]). However, little is known about either the TCR repertoire specific for this epitope or the molecular basis for this observed immunodominance. The EBV_RPP CD8⁺ T cell response was common among both EBV-seropositive HLA-B*07:02⁺ healthy and immunocompromised individuals. Similar TCRs were identified in EBV_RPP-specific CD8⁺ T cell repertoires across multiple HLA-B7⁺ individuals, indicating a shared Ag-driven bias in TCR usage. In particular, TRBV4-1 and TRAV38 usage was observed in five out of six individuals studied. In this study, we report the crystal structure of a TRBV4-1⁺ TCR-HLA-B*07:02/EBV_RPP complex, which provides a molecular basis for the observed TRBV4-1 bias. These findings enhance our understanding of the CD8⁺ T cell response toward a common EBV determinant in HLA-B*07:02⁺ individuals.