title: Increasing viral dose causes a reversal in CD8+ T cell immunodominance during primary influenza infection due to differences in antigen presentation, T cell avidity, and precursor numbers.
abstract: T cell responses are characterized by the phenomenon of immunodominance (ID), whereby peptide-specific T cells are elicited in a reproducible hierarchy of dominant and subdominant responses. However, the mechanisms that give rise to ID are not well understood. We investigated the effect of viral dose on primary CD8(+) T cell (T(CD8+)) ID by injecting mice i.p. with various doses of influenza A virus and assessing the primary T(CD8+) response to five dominant and subdominant peptides. Increasing viral dose enhanced the overall strength of the T(CD8+) response, and it altered the ID hierarchy: specifically, NP(366-374) T(CD8+) were dominant at low viral doses but were supplanted by PA(224-233) T(CD8+) at high doses. To understand the basis for this reversal, we mathematically modeled these T(CD8+) responses and used Bayesian statistics to obtain estimates for Ag presentation, T(CD8+) precursor numbers, and avidity. Interestingly, at low viral doses, Ag presentation most critically shaped ID hierarchy, enabling T(CD8+) specific to the more abundantly presented NP(366-374) to dominate. By comparison, at high viral doses, T(CD8+) avidity and precursor numbers appeared to be the major influences on ID hierarchy, resulting in PA(224-233) T(CD8+) usurping NP(366-374) cells as the result of higher avidity and precursor numbers. These results demonstrate that the nature of primary T(CD8+) responses to influenza A virus is highly influenced by Ag dose, which, in turn, determines the relative importance of Ag presentation, T(CD8+) avidity, and precursor numbers in shaping the ID hierarchy. These findings provide valuable insights for future T(CD8+)-based vaccination strategies.
authors.affiliation: Infection and Inflammation Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Fabio
authors.initials: F
authors.lastname: Luciani
authors.forename: Megan T
authors.initials: MT
authors.lastname: Sanders
authors.forename: Sara
authors.initials: S
authors.lastname: Oveissi
authors.forename: Ken C
authors.initials: KC
authors.lastname: Pang
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018655:Lymphocyte Count; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D010455:Peptides / Q000008:administration & dosage; D013234:Stem Cells / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000821:virology; D019562:Viral Load / Q000276:immunology*
chemical_list: D016056:Immunodominant Epitopes; D010455:Peptides