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 IMPORTANCEIsolates 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. Binding specificity among polyomaviruses is determined by interaction of the VP1 major capsid protein with host cell gangliosides having particular terminal sialic acid linkages (1). The gangliosides GD1a and GT1b are required for transport of mouse polyomavirus (MPyV) to the endoplasmic reticulum (2, 3). Discrete amino acid differences in the receptor binding site of VP1 impart important biological differences, including profound differences in pathogenicity (4). Replacement of the glycine (G) at position 91 of VP1 of the laboratory-derived small-plaque (SP) MPyV strain RA with glutamic acid (E), the amino acid at this position in the naturally occurring large-plaque (LP) strain PTA, was sufficient to convert it into a strain with an LP morphology and to alter the profile of induced tumors from a mesenchymal to an epithelial cell lineage (5). Alternatively, substitution of G for E at position 91 in VP1 in PTA had the opposite effect on plaque size and tumorigenicity (6, 7). In SP strains, VP1 capsids with G-91 interact with branched (␣-2,6)-linked sialyloligosaccharides, which may act as pseudoreceptors by binding cell surface glycoproteins that divert virions into noninfectious pathways (8). An E at this position in VP1 leads to electrostatic repulsion of the (␣-2,6)-linked sialic acids, thereby preventing binding of such branched structures by LP strains; however, binding to gangliosides with sialic acid (␣-2,3)-linked to galactose is retained for virion uptake into an infectious pathway (9, 10). Interestingly, MPyVs isolated from feral mice have exclusively E-91 VP1s, an unexpected finding given that such LP viruses are potentially more oncogenic than G-91 SP viruses (11).The human polyomavirus JC virus (JCV) is a frequent member of the human virome (12). Mutations of JCV capsid protein VP1

CD4 T cells control development and maintenance of brain-resident CD8 T cells during polyomavirus infection

“…Virus-specific CD8 T cells control infections in the CNS via cytopathic and non-cytopathic effector mechanisms [ 70 ]. We previously reported that MuPyV infection was controlled in mice lacking TNF receptors or perforin and/or Fas as efficiently as in WT mice, and that IFN-γ and IFN-I inhibited MuPyV replication in vivo [ 32 , 33 , 71 ]. Likewise, IFN-γ and IFN-I inhibited JCPyV replication in established human glial cell lines and primary human glial cells [ 72 , 73 ].…”

Infectious Sporozoites of Plasmodium berghei Effectively Activate Liver CD8α+ Dendritic Cells

“…The key functions of type I IFN response involve activation and differentiation of DCs by promoting the expression of MHC molecules and various costimulatory molecules for the priming of T cells ( 34 , 60 ). Furthermore, type I interferons promote the cross-presentation of antigen to the CD8 + T cells ( 47 , 61 ) and are known to favor formation of memory CD8 + T cells ( 62 ). As CD8α + DCs are preferred APCs for cross-presentation, it is possible that the Inf.…”

CD8 T Cells and STAT1 Signaling Are Essential Codeterminants in Protection from Polyomavirus Encephalopathy

“…Mouse polyomavirus (MuPyV) and JCPyV have similar genomic and structural features and both establish persistent, asymptomatic infections in their natural hosts that are controlled by adaptive immunity (21,22). We reported that IFN-␥ and type I IFNs mediate viral control in the kidney and spleen (23,24). Here, we sought to determine whether type I, II, or III IFNs or STAT1 confer protection against MuPyV pathogenesis in the brain.…”