title: Precursor frequency and competition dictate the HLA-A2-restricted CD8+ T cell responses to influenza A infection and vaccination in HLA-A2.1 transgenic mice.
abstract: The human HLA-A2-restricted CD8(+) T cell response to influenza A virus (IAV) is largely directed against the matrix protein-derived M1(58-66) epitope and represents an archetypal example of CD8(+) T cell immunodominance. In this study, we examined the CD8(+) T cell hierarchy to M1(58-66) and two subdominant IAV-specific epitopes: NS1(122-130) and PA(46-55) in HLA-A2(+) human subjects and HLA-A2.1 transgenic (HHD) mice. Using epitope-based lipopeptides, we show that the CD8(+) T cell hierarchy induced by IAV infection could also be induced by lipopeptide vaccination in a context outside of viral infection when the Ag load is equalized. In the HHD HLA-A2.1 mouse model, we show that the naive T cell precursor frequencies, and competition at the Ag presentation level, can predict the IAV-specific CD8(+) T cell hierarchy. Immunization of mice with subdominant epitopes alone was unable to overcome the dominance of the M1(58-66)-specific response in the face of IAV challenge; however, a multiepitope vaccination strategy was most effective at generating a broad and multispecific response to infection.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Amabel C L
authors.initials: AC
authors.lastname: Tan
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000494:pharmacology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D055666:Lipopeptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D014611:Vaccination; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C085820:INS1 protein, influenza virus; D007252:Influenza Vaccines; D055666:Lipopeptides; D017361:Viral Nonstructural Proteins