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

J Immunol. 2013 Jan 1;190(1):36-47. doi: 10.4049/jimmunol.1200089. Epub 2012 Dec 10.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / 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*

Substances

  • Immunodominant Epitopes
  • Peptides