Impact of clonal competition for peptide-MHC complexes on the CD8 ⁺ T-cell repertoire selection in a persistent viral infection

CD8+ T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)-specific CD8+ T-cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public T-cell repertoire or a private yet diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public TCR was coincident with an atypical MHC-peptide structure, in that the epitope adopted a helical conformation that bulged from the Ag-binding groove, whilst a diverse TCR profile was observed in response to the epitope that formed a flatter, more featureless landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared to the T-cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its phenotype.