title: A virus-specific CD8+ T cell immunodominance hierarchy determined by antigen dose and precursor frequencies.
abstract: Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8(+) T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus nucleoprotein (NP(366-374)) and acid polymerase (PA(224-233)) peptides presented by H2D(b) have been analyzed by disabling (N5--> Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral context resulted in an apparent equalization of D(b)NP(366) [epitope consisting of viral nucleoprotein (NP) amino acid residues 366-374 complexed with the H2D(b) MHC class I glycoprotein] and D(b)PA(224) (H2D(b)+PA(224-233)) epitope abundance after direct infection in vitro and induced reproducible changes in the magnitude of the D(b)NP(366)- and D(b)PA(224)-specific T cell subsets generated after infection of mice. Comparison of D(b)NP(366)- and D(b) PA(224)-specific CD8(+) T cell responses induced from the native configuration and from the viral neuraminidase stalk demonstrated that the size of both primary and secondary responses is influenced by relative epitope levels and that, at least after secondary challenge, the magnitude of responses is also determined by CD8(+) T cell precursor frequency. Thus, this immunodominance hierarchy is a direct function of antigen dose and T cell numbers.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Australia.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.forename: Ken
authors.initials: K
authors.lastname: Pang
authors.forename: Richard
authors.initials: R
authors.lastname: Webby
authors.forename: Miles
authors.initials: M
authors.lastname: Davenport
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
mesh_terms: D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000378:metabolism*; D000956:Antigens, Viral / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D005260:Female; D007107:Immune System; D007156:Immunologic Memory / Q000276:immunology; D008168:Lung / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D009698:Nucleoproteins / Q000737:chemistry; D009975:Orthomyxoviridae / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D000941:Antigens; D000956:Antigens, Viral; D016207:Cytokines; D000939:Epitopes; D009698:Nucleoproteins; D010455:Peptides; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D014764:Viral Proteins