Epitope specificity of memory CD8+ T cells dictates vaccination-induced mortality in LCMV-infected perforin-deficient mice |
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Authors: | Pham Nhat-Long L Badovinac Vladimir P Harty John T |
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Institution: | Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA. |
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Abstract: | 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 NP118‐126 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. |
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Keywords: | Animal models CD8+ T cells Cytotoxicity Vaccination |
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