Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells

<h2>Summary</h2> Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8⁺ T cell differentiation. During acute infection, naive to effector CD8⁺ T cell differentiation was accompanied by a transient loss of DNA methylation of the <i>Pdcd1</i> locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with <i>Pdcd1</i> remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the <i>Pdcd1</i> regulatory region was completely demethylated in exhausted CD8⁺ T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the <i>Pdcd1</i> locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.