- Restrictions on Access:
- Restricted (PSU only).
- Polyomaviruses (PyVs), normally asymptomatic members of the virome of most vertebrate species (including humans), can cause debilitating diseases in the setting of dampened immune status. In particular, the human JCPyV is the causative agent of several high-mortality CNS diseases, of which progressive multifocal leukencephalopathy (PML) has the highest incidence. Loss of CD4 T cells, CD8 T cells, and B cells/antibodies have all been implicated in the pathogenesis of PML; however, CD4 T cells in particular have been associated with an increased risk for disease. CD4 T cells provide help to both CD8 T cells and B cells during antiviral immune responses. The overall goal of this work was to define the mechanism(s) of CD4 T cell help against PyVs for the antiviral CD8 T cell and B cell/antibody responses using murine (Mu)PyV. When mice are inoculated with MuPyV intracranially (i.c.), they develop a PyV-induced encephalitis complete with T cell infiltration and demyelination of the white matter tracts. CD8 T cells in the brain have been associated with protection against JCPyV-induced brain pathology. Given the tissue environment of the brain, antiviral CD8 T cells must balance viral control with immune-mediated damage. These cells require differentiation into a specific subset of immune memory cells designated as brain resident memory (bTRM). We recently demonstrated that development of bTRM is CD4 T cell dependent, i.e. CD8 T cells that develop in the absence of CD4 T cells (unhelped) do not become bTRM. I identified CD4 T cell-derived interleukin-21 (IL-21) as the key factor for establishing CD8 bTRM. Of the CD4 T cells in the brain, those with the CXCR5hiPD-1hi phenotype were found to be the primary source of IL-21. The IL-21-producing CD4 T cells in the brain also had the highest affinity TCRs. CD8 T cells lacking IL-21 receptors (IL21R-/-) failed to become bTRM, and IL-21 treatment during CD4 T cell deficiency mitigated several of the defects seen in unhelped CD8 T cells, supporting IL-21 as the source of CD4 T cell help. As JCPyV is primarily a kidney tropic virus, outstanding questions in the field have centered around its ability to infect the brain. JCPyVs isolated from the blood, CSF, and brains of PML patients have discrete amino acid substitutions in their receptor binding domain of VP1, the major capsid protein. These mutations were originally thought to confer neurotropism, but the mutant JCPyVs infected glial cell at equivalent levels to the WT JCPyV. More recent data showed that the sera of PML patients were unable to neutralize their mutant JCPyV, suggesting these mutations conferred escape from humoral immunity. JCPyV-specific CD4 T cells have been shown to be critical in controlling JCPyV infection and preventing development of PML. MuPyV has been shown to induce a neutralizing IgG response in the absence of T cells. We isolated a VP1 monoclonal antibody that neutralized parental MuPyV but failed to neutralize MuPyV with a sequence-equivalent JCPyV-PML VP1 mutation. I tested the hypothesis that the T-independent VP1 antibody response would neutralize parental MuPyV but fail to neutralize this mutant MuPyV. I show that sera from MuPyV-infected CD4 T cell-deficient and IL21R-/- mice is less efficient than sera from MuPyV-infected WT mice in binding the VP1 mutant virus than the parental MuPyV. Collectively, these data suggest that skewing toward a T-independent antibody response may allow outgrowth of JCPyV VP1 mutants that evade recognition by neutralizing antibodies and set the stage for PML development.
- Dissertation Note:
- Ph.D. Pennsylvania State University 2020.
- Technical Details:
- The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
View MARC record | catkey: 31803975