title: Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy.
abstract: Understanding T cell immunodominance hierarchies is fundamental to the development of cellular-based vaccines and immunotherapy. A combination of influenza virus infection in C57BL/6J mice and reverse genetics is used here to dissect the role of T cell antigen receptor (TCR) repertoire in the immunodominant D(b)NP(366)CD8(+) T cell response. Infection with an engineered virus (NPM6A) containing a single alanine (A) mutation at the critical p6 NP(366-374) residue induced a noncross-reactive CD8(+) T cell response characterized by a novel, narrower TCR repertoire per individual mouse that was nonetheless equivalent in magnitude to that generated after WT virus challenge. Although of lower overall avidity, the levels of both cytotoxic T lymphocyte activity and cytokine production were comparable with those seen for the native response. Importantly, the overdominance profile characteristic of secondary D(b)NP(366)-specific clonal expansions was retained for the NPM6A mutant. The primary determinants of immunodominance in this endogenous, non-TCR-transgenic model of viral immunity are thus independent of TCR repertoire composition and diversity. These findings both highlight the importance of effective antigen dose for T cell vaccination and/or immunotherapy and demonstrate the feasibility of priming the memory T cell compartment with engineered viruses to protect against commonly selected mutants viral (or tumor) escape mutants.
authors.affiliation: Department of Microbiology and Immunology, The Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, Melbourne, Australia. kkedz@unimelb.edu.au
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.forename: Carole
authors.initials: C
authors.lastname: Guillonneau
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Hatton
authors.forename: Richard
authors.initials: R
authors.lastname: Webby
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D000939:Epitopes / Q000276:immunology; D005818:Genetic Engineering; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism
chemical_list: D000939:Epitopes; D016056:Immunodominant Epitopes; D007252:Influenza Vaccines; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta