Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology
Fei Liu, … , Daniel E. Hassett, J. Lindsay Whitton
Fei Liu, … , Daniel E. Hassett, J. Lindsay Whitton
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):465-475. https://doi.org/10.1172/JCI25608.
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Research Article Virology

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

Abstract

CD8+ T cells play a key role in clearing primary virus infections and in protecting against subsequent challenge. The potent antiviral effects of these cells make them important components of vaccine-induced immunity and, because of this, peptide vaccines often contain epitopes designed to induce strong CD8+ T cell responses. However, the same effector functions that protect the host also can be harmful if they are not tightly regulated, and virus-specific CD8+ T cells are a frequent cause of immunopathology. Here, we report that the administration of peptide to virus-immune recipient mice can lead to the synchronous activation of preexisting virus-specific CD8+ T cells with serious, and even lethal, consequences. Mice infected with LCMV or vaccinia virus developed rapid and profound hypothermia following injection of cognate synthetic peptides, and LCMV-infected mice frequently died within hours. Detailed analyses of the LCMV infected mice revealed enterocyte apoptosis and implicated TNF produced by peptide-specific CD8+ T cells as the major mediator of disease. The caspase inhibitor zVADfmk had no demonstrable effect on the development of hypothermia, but diminished enterocyte apoptosis and greatly reduced the number of deaths. These findings, if similarly observed in patients, counsel caution when administering powerful immunogens such as peptide vaccines to individuals who may have a large preexisting pool of epitope-specific CD8+ T cells.

Authors

Fei Liu, Ralph Feuer, Daniel E. Hassett, J. Lindsay Whitton

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Figure 6

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Clinical effects of peptide injection do not occur in mice lacking TNFR1...
Clinical effects of peptide injection do not occur in mice lacking TNFR1. (A) C57BL/6 or TNFR1KO mice (4 per group) were infected with LCMV and, 8 days later, were sacrificed, and their virus-specific CD8+ T cell responses were measured by ICCS, as described in Methods. Dot plots are gated on CD8+ T cells; the y axis shows IFN-γ staining, and the x axis shows TNF staining. Numbers in each of 3 quadrants indicate the CD8+ T cells in that quadrant as a percentage of total CD8+ T cells. (B) C57BL/6 or TNFR1KO mice (8 per group) were microchip-implanted, and infected with LCMV. Eight days later, the mice were injected either with peptide (6 mice per group, open symbols, dotted lines) or with saline (2 mice per group, filled symbols, solid lines), and their body temperatures were measured over the subsequent 8 hours. Crosses indicate deaths that occurred before the end of this period.