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

Nhat Long L Pham, Vladimir P. Badovinac, John T. Harty

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1488-1499
Number of pages12
JournalEuropean Journal of Immunology
Volume42
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

Lymphocytic choriomeningitis virus
Epitopes
Vaccination
T-Lymphocytes
Mortality
Perforin
Virus Diseases
Vaccines
Hemophagocytic Lymphohistiocytosis
Immunodominant Epitopes
mouse perforin
Infection
Cytokines
Viruses

Keywords

  • Animal models
  • CD8 T cells
  • Cytotoxicity
  • Vaccination

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Epitope specificity of memory CD8 + T cells dictates vaccination-induced mortality in LCMV-infected perforin-deficient mice. / Pham, Nhat Long L; Badovinac, Vladimir P.; Harty, John T.

In: European Journal of Immunology, Vol. 42, No. 6, 01.06.2012, p. 1488-1499.

Research output: Contribution to journalArticle

Pham, Nhat Long L ; Badovinac, Vladimir P. ; Harty, John T. / Epitope specificity of memory CD8 + T cells dictates vaccination-induced mortality in LCMV-infected perforin-deficient mice. In: European Journal of Immunology. 2012 ; Vol. 42, No. 6. pp. 1488-1499.
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