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

• Published in: The Journal of immunology (1950) 2013-01, Vol.190 (1), p.36-47
• Main Authors: Luciani, Fabio, Sanders, Megan T, Oveissi, Sara, Pang, Ken C, Chen, Weisan
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Dose-Response Relationship, Immunologic; Female; Humans; Immunodominant Epitopes - immunology; Influenza A virus; Influenza A virus - immunology; Influenza, Human - immunology; Influenza, Human - metabolism; Influenza, Human - pathology; Lymphocyte Count; Lymphocytic choriomeningitis virus - immunology; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred C57BL; Models, Immunological; Peptides - administration & dosage; Stem Cells - immunology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - virology; Viral Load - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200089

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.