Abstract
Abstract Progressive loss of antiviral functions in antigen-specific CD8 T cell during chronic infection is caused by continuous upregulation and signaling by immunoinhibitory receptors including Programmed Death 1(PD-1). Using human and murine model systems of acute and chronic viral infections, we found that differentiation of naïve CD8 T cells into effector cells during acute infection was accompanied by a transient loss of DNA methylation of the PD-1 locus. Viral clearance and the subsequent effector to memory differentiation resulted in memory-specific DNA remethylation of the PD-1 locus. Conversely, chronic infection induced complete and sustained DNA demethylation of the PD-1 regulatory region in exhausted CD8 T cells. Surprisingly, reduction of virus levels and PD-1 expression in chronically infected animals did not result in remethylation and coincided with decreased expression of a specific de novo methyltransferase (Dnmt3a) isoform. The unmethylated PD-1 locus allowed for rapid PD-1 re-expression, potentially prematurely terminating antiviral functions. These studies provide a foundation for efforts towards reprogramming of PD-1 expression to rejuvenate exhausted T cells.
Published Version
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