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.