| First Author | Pham NL | Year | 2012 |
| Journal | Eur J Immunol | Volume | 42 |
| Issue | 6 | Pages | 1488-99 |
| PubMed ID | 22678903 | Mgi Jnum | J:187759 |
| Mgi Id | MGI:5438161 | Doi | 10.1002/eji.201142263 |
| Citation | Pham NL, et al. (2012) Epitope specificity of memory CD8+ T cells dictates vaccination-induced mortality in LCMV-infected perforin-deficient mice. Eur J Immunol 42(6):1488-99 |
| abstractText | Perforin-deficient (PKO) mice serve as models for familial hemophagocytic lympho-histiocytosis, a uniformly fatal disease associated with viral infection of perforin-deficient humans. Naive 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-gamma, 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. |
