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
- Author(s)
- Luciani, F; Sanders, MT; Oveissi, S; Pang, KC; Chen, WS;
- Details
- Publication Year 2013-01-01,Volume 190,Issue #1,Page 36-47
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Publication Type
- Journal Article
- 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 (TCD8+) ID by injecting mice i.p. with various doses of influenza A virus and assessing the primary TCD8+ response to five dominant and subdominant peptides. Increasing viral dose enhanced the overall strength of the TCD8+ response, and it altered the ID hierarchy: specifically, NP366-374 TCD8+ were dominant at low viral doses but were supplanted by PA(224-233) TCD8+ at high doses. To understand the basis for this reversal, we mathematically modeled these TCD8+ responses and used Bayesian statistics to obtain estimates for Ag presentation, TCD8+ precursor numbers, and avidity. Interestingly, at low viral doses, Ag presentation most critically shaped ID hierarchy, enabling TCD8+ specific to the more abundantly presented NP366-374 to dominate. By comparison, at high viral doses, TCD8+ avidity and precursor numbers appeared to be the major influences on ID hierarchy, resulting in PA(224-233) TCD8+ usurping NP366-374 cells as the result of higher avidity and precursor numbers. These results demonstrate that the nature of primary TCD8+ responses to influenza A virus is highly influenced by Ag dose, which, in turn, determines the relative importance of Ag presentation, TCD8+ avidity, and precursor numbers in shaping the ID hierarchy. These findings provide valuable insights for future TCD8+-based vaccination strategies. The Journal of Immunology, 2013, 190: 36-47.
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- APPROXIMATE BAYESIAN COMPUTATION; VIRUS-SPECIFIC CTL; CLASS-I; REPERTOIRE DIVERSITY; A VIRUS; BINDING-AFFINITY; CLONAL EXPANSION; LYMPH-NODE; RESPONSES; EPITOPE
- Research Division(s)
- Inflammation
- Publisher's Version
- https://doi.org/10.4049/jimmunol.1200089
- Terms of Use/Rights Notice
- Copyright © 2012 by The American Association of Immunologists, Inc.
Creation Date: 2013-01-01 12:00:00