Mouse polyomavirus-specific CD8+ T cells establish a brain-resident memory population during persistent infection (VIR6P.1174)

Abstract

Abstract Human JC polyomavirus (JCV) causes progressive multifocal leukoencephalopathy (PML), a rare but life-threatening demyelinating disease in patients under profound immunosuppression and those receiving therapeutic immunomodulation for autoimmune and inflammatory disorders. Using persistent mouse polyomavirus (MPyV) infection in mice, we are developing a model of PyV-induced CNS disease to elucidate the role of immunosuppression in PML pathogenesis. Histology revealed corpus callosum demyelination in 100% of persistently infected mice. Following intracerebral injection with MPyV, immunocompetent C57BL/6 mice showed robust infiltration by MPyV-specific CD8 T cells with minimal contraction. During persistent CNS infection, a significant population of CD8 T cells exhibited a tissue-resident memory (Trm) phenotype (CD103+CD69+CD62Llo), as reported for acute VSV and latent HSV-1 infections, and incorporated BrdU in situ, suggesting capacity for self-renewal. Furthermore, these Trm cells develop and survive independently of replenishment by circulating antiviral CD8 T cells or CD4 T cell help. Unlike in the spleen, MPyV-specific CD8 T cells are PD-1hi upon infiltration of the brain without evidence of exhaustion. Interestingly, levels of CD8 and T cell receptor also increase on cells in the brain over time. Whether brain-infiltrating T cells exhibit higher sensitivity to antigen due to higher affinity and/or functional avidity is currently under investigation.