title: Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection.
abstract: 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, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)-peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while 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 with 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.
authors.affiliation: Australian Centre for Vaccine Development and Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Wynn
authors.forename: Zara
authors.initials: Z
authors.lastname: Fulton
authors.forename: Leanne
authors.initials: L
authors.lastname: Cooper
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Silins
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Julia K
authors.initials: JK
authors.lastname: Archbold
authors.forename: Fleur E
authors.initials: FE
authors.lastname: Tynan
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002460:Cell Line; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000956:Antigens, Viral; D022801:Complementarity Determining Regions; D000939:Epitopes; D015235:HLA-B Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell