title: A quantitative analysis of the variables affecting the repertoire of T cell specificities recognized after vaccinia virus infection.
abstract: Many components contribute to immunodominance in the response to a complex virus, but their relative importance is unclear. This was addressed using vaccinia virus and HLA-A*0201 as the model system. A comprehensive analysis of 18 viral proteins recognized by CD8(+) T cell responses demonstrated that approximately one-fortieth of all possible 9- to 10-mer peptides were high-affinity HLA-A*0201 binders. Peptide immunization and T cell recognition data generated from 90 peptides indicated that about one-half of the binders were capable of eliciting T cell responses, and that one-seventh of immunogenic peptides are generated by natural processing. Based on these results, we estimate that vaccinia virus encodes approximately 150 dominant and subdominant epitopes restricted in by HLA-A*0201. However, of all these potential epitopes, only 15 are immunodominant and actually recognized in vivo during vaccinia virus infection of HLA-A*0201 transgenic mice. Neither peptide-binding affinity, nor complex stability, nor TCR avidity, nor amount of processed epitope appeared to strictly correlate with immunodominance status. Additional experiments suggested that vaccinia infection impairs the development of responses directed against subdominant epitopes. This suggested that additional factors, including immunoregulatory mechanisms, restrict the repertoire of T cell specificities after vaccinia infection by a factor of at least 10.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Assarsson
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Carla
authors.initials: C
authors.lastname: Oseroff
authors.forename: Valerie
authors.initials: V
authors.lastname: Pasquetto
authors.forename: Huynh-Hoa
authors.initials: HH
authors.lastname: Bui
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Howard
authors.initials: H
authors.lastname: Grey
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins