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.

Long Peptide Vaccination Can Lead to Lethality through CD4+ T Cell-Mediated Cytokine Storm

“…A similar phenomenon was described in a CD8 T cell system in which boost of lymphocytic choriomeningitis virus-immune mice with an immunodominant epitope peptide induced death (40). Pathological modifications were seen in the gut with mucus expulsion by the goblet cells.…”

“…The dying mice showed symptoms consistent with TNF-arelated toxicity, as was observed after peptide restimulation of viral or tumoral peptide specific memory CD8 T cell (40,47). In contrast to septic shock syndrome (48), serum levels of IL-1 after LP boost did not increase (data not shown), whereas TNF-a and IL-6 levels were very high.…”

“…No histopathological changes were observed in other organs. These data suggest that the symptoms and death induced by LP vaccination are caused by a cytokine storm with associated immunopathology (40,45).…”

“…Administration of viral peptide to virus-immune mice can lead to rapid activation of preexisting virus-specific CD8 T cells with high lethality (40), induced by TNF-a secreted by the peptide-specific CD8 T cells. To our knowledge, there have been no reports that activation of Ag-specific CD4 T cells can lead to serious or lethal consequences.…”

Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus

“…These unique properties of memory T cells enable them to mediate protective immunity, yet they can also predispose them to promote immunopathology in antiviral immunity (1,2), autoimmunity (3), and transplantation (4). Regulation of memory T cell-mediated responses is therefore a critical consideration for T cell-directed immunotherapies to optimize their protective abilities and inhibit deleterious consequences.…”