Submitted November 8, 2007
Accepted February 2, 2008
Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection
Katherine K. Wynn, Zara Marland, Leanne Cooper, Sharon L. Silins, Stephanie Gras, Julia K. Archbold, Fleur E. Tynan, John J. Miles, James McCluskey, Scott R. Burrows, Jamie Rossjohn, and Rajiv Khanna*
Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Australia
Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, School of Biomedical Sciences, Monash University, Clayton, Australia
School of Medicine, University of Queensland, Brisbane, Australia
Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia
* Corresponding author; email: rajiv.khanna{at}qimr.edu.au.
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.
