Date

May 2011

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

Lymphocytic choriomeningitis virus (LCMV) is a natural mouse pathogen, and acute infection of adult mice induces a robust and protective CD8[superscript +] T cell response that persists for the life of the animal. These attributes make murine LCMV infection an ideal model in which to develop and test vaccine strategies designed to elicit CD8[superscript +] T cell immunity. In these studies, vaccination of adult C57BL/6 mice with hydrogen peroxide (H[subscript 2]0[subscript 2])-inactivated whole LCMV virions results in the production of CD8[superscript +] T cell immunity with an altered immunodominance hierarchy relative to infection with acute or chronic LCMV strains. Higher percentages of vaccine-induced CD8[superscript +] T cells express multiple effector cytokines relative to infection-induced CD8[superscript +] T cells, and this enhanced memory-type cytokine expression profile is present as early as 8 days following vaccination. H[subscript 2]0[subscript 2]-LCMV vaccination was sufficient to protect mice from chronic LCMV infection following challenge with the chronic viral variant, LCMV-Clone 13, and this protection was mediated directly by CD8[superscript +] T cells. Further investigations, including vaccinations with individual LCMV peptides, revealed a high degree of cross-reactivity between LCMV peptides that had little or no sequence homology. This level of cross-reactivity among peptides derived from a single virus has not been previously observed. This work demonstrates that it is possible to achieve durable and protective CD8[superscript +] T cell-based immunity using an H[subscript 2]0[subscript 2]-inactivated whole virus vaccine, and reveals previously undescribed crossreactivity among multiple LCMV-specific CD8[superscript +] T cell populations.

Identifier

doi:10.6083/M4251G61

School

School of Medicine

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