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.
Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
Nhat-Long L
NL
Pham
Vladimir P
VP
Badovinac
John T
JT
Harty
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte; D007156:Immunologic Memory; D008216:Lymphocytic Choriomeningitis / Q000401:mortality*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency* / Q000502:physiology; D014611:Vaccination / Q000009:adverse effects*; D014765:Viral Vaccines / Q000009:adverse effects* / Q000276:immunology
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D052899:Pore Forming Cytotoxic Proteins; D014765:Viral Vaccines; C483886:perforin, mouse