Epitope specificity of memory CD8⁺T cells dictates vaccination‐induced mortality in LCMV‐infected perforin‐deficient mice

Perforin-deficient (PKO) mice serve as models for familial hemophagocytic lympho-histiocytosis, a uniformly fatal disease associated with viral infection of perforin-deficient humans. Naïve perforin-deficient BALB/c mice survive while vaccinated PKO mice containing virus-specific memory CD8(+) T cells rapidly succumb to lymphocytic choriomeningitis virus (LCMV) infection. Thus, vaccination converts a nonlethal persistent infection into a fatal disease mediated by virus-specific memory CD8(+) T cells. Here, we determine the extent to which vaccination-induced mortality in PKO mice following LCMV challenge is due to differences in vaccine modalities, the quantity or epitope specificity of memory CD8(+) T cells. We show that LCMV-induced mortality in immune PKO mice is independent of vaccine modalities and that the starting number of memory CD8(+) T cells specific to the immunodominant epitope NP(118-126) dictates the magnitude of secondary CD8(+) T-cell expansion, the inability to regulate production of CD8(+) T-cell-derived IFN-γ, and mortality in the vaccinated PKO mice. Importantly, mortality is determined by the epitope specificity of memory CD8(+) T cells and the associated degree of functional exhaustion and cytokine dysregulation but not the absolute magnitude of CD8(+) T-cell expansion. These data suggest that deeper understanding of the parameters that influence the outcome of vaccine-induced diseases would aid rational vaccine design to minimize adverse outcomes after infection.