title: Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner.
abstract: Mouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference at position 91 of the VP1 capsid protein shifts the profile of tumors induced by MPyV from an epithelial to a mesenchymal cell origin. Here we asked if this tropism difference affects the MPyV-specific CD8 T cell response, which controls MPyV infection and tumorigenesis. Infection by the laboratory MPyV strain RA (VP1-91G) or a strain A2 mutant with an E-to-G substitution at VP1 residue 91 [A2(91G)] generated a markedly smaller virus-specific CD8 T cell response than that induced by A2(VP1-91E) infection. Mutant A2(91G)-infected mice showed a higher frequency of memory precursor (CD127(hi) KLRG1(lo)) CD8 T cells and a higher recall response than those of A2-infected mice. Using T cell receptor (TCR)-transgenic CD8 T cells and immunization with peptide-pulsed dendritic cells, we found that early bystander inflammation associated with A2 infection contributed to recruitment of the larger MPyV-specific CD8 T cell response. Beta interferon (IFN-β) transcripts were induced early during A2 or A2(91G) infections. IFN-β inhibited replication of A2 and A2(91G) in vitro Using mice lacking IFN-αβ receptors (IFNAR(-/-)), we showed that type I IFNs played a role in controlling MPyV replication in vivo but differentially affected the magnitude and functionality of virus-specific CD8 T cells recruited by A2 and A2(91G) viral infections. These data indicate that type I IFNs are involved in protection against MPyV infection and that their effect on the antiviral CD8 T cell response depends on capsid-mediated tropism properties of the MPyV strain.
  
  
  
  Isolates of the human polyomavirus JC virus from patients with the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML) carry single amino acid substitutions in the domain of the VP1 capsid protein that binds the sialic acid moiety of glycoprotein/glycolipid receptors on host cells. These VP1 mutations may alter neural cell tropism or enable escape from neutralizing antibodies. Changes in host cell tropism can affect recruitment of virus-specific CD8 T cells. Using mouse polyomavirus, we demonstrate that a single amino acid difference in VP1 known to shift viral tropism profoundly affects the quantity and quality of the anti-polyomavirus CD8 T cell response and its differentiation into memory cells. These findings raise the possibility that CD8 T cell responses to infections by human polyomaviruses may be influenced by VP1 mutations involving domains that engage host cell receptors.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Qingsong
authors.identifier: 0000-0001-7509-3027
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.identifier: 0000-0002-5069-603X
authors.lastname: Shwetank
authors.affiliation: Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, Georgia, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Frost
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Saumya
authors.identifier: 0000-0002-9548-3505
authors.initials: S
authors.lastname: Maru
authors.forename: Aron E
authors.identifier: 0000-0002-7969-2841
authors.initials: AE
authors.lastname: Lukacher
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D011120:Polyomavirus / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D056189:Viral Tropism; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; D016207:Cytokines; D007370:Interferon Type I; D011948:Receptors, Antigen, T-Cell; C062481:VP1 protein, polyomavirus; D016899:Interferon-beta