Abstract
Abstract Mouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. Human JC polyomavirus variants associated with progressive multifocal leukoencephalopathy have discrete amino acid mutations in VP1, the major capsid protein, that affects tropism for glial cells. A glutamic acid (E) to glycine (G) difference at position 92 of VP1, shifts the profile to tumors induced by MPyV from epithelial to mesenchymal cell origin. Here, we asked if this shift in tropism affects the MPyV-specific CD8 T cell response, which controls MPyV infection/tumorigenesis. We found that the A2 (92E-VP1) and RA (92G-VP1) MPyV strains differ sharply in MPyV-specific CD8 T cell responses. A2 virus generates a robust, high magnitude virus-specific CD8 T cell response, whereas RA virus elicits a markedly smaller anti-MPyV CD8 T cell response. Infection by an A2 92G-VP1 mutant virus recapitulates the antiviral CD8 T cell response seen with RA virus. Notably, the antiviral CD8 T cell recall response during persistent infection by this A2 mutant significantly exceeded that of A2 virus. Using immunization with peptide-loaded dendritic cells in the setting of bystander inflammation by A2 or the mutant virus, we found that A2 virus stimulates a higher magnitude MPyV-specific CD8 T cell response; this difference is negated in DC-deficient Flt3-/- mice. Together, these data indicate that viral tropism for DCs is a major determinant of the quantity and quality of the anti-MPyV CD8 T cell response.
Published Version
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