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

Abstract

SUMMARY Functionally exhausted T cells express high levels of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. 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, naïve to effector CD8 T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of TCR signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 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 Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

“…Interestingly, among differentially methylated genes was also HNRNPLL, involved in alternative splicing of CD45 to the Tmem signature isoform CD45RO, and the two homing-related receptors, SELL (L-selectin) and CCR7, suggesting that the permanent change in the recirculation pattern with transition from Tcm to Tem is epigenetically fixed. For others, concordant epigenetic changes have already been described in murine CD8 + T cells (e.g., BATF, LEF1, PDCD1, TBX21, TCF7, ZBTB32;Scharer et al, 2013;Youngblood et al, 2011;Hashimoto et al, 2013).…”

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

“…We know that PD‐1 expression in CD8 + T cells results from chronic antigenic exposure in the tumour tissue [37]. However, recent evidence describes that in the case of chronic infection, permanent PD‐1 expression in T RM cells is imprinted epigenetically and is antigen‐independent [38, 39]. Additionally, PD‐1 signalling has been demonstrated to be important for antigen‐independent maintenance of memory CD8 + T cells [40].…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…This stability of the exhausted phenotype is supported by epigenetic studies showing that chronic LCMV clone-13 infections induce profound and permanent de-methylations in the PD-1 promoter region. The de-methylation was maintained in antigen-specific T-cells long after LCMV clone-13 virus load has dropped below detectable levels in the blood 65 . A lack of methylation in the PD-1 promoter region has also been observed among antigen-specific CD8 T-cells from HIV patients which have been treated long-term (>2 years) with anti-retroviral therapy or in elite controllers 66 What remains unknown, however, is when T-cells undergo this differentiation.…”

“…So far, the reduced ability of T-cells to produce cytokines in chronic infections has been seen as a sign of deteriorating T-cell function but this phenotype could also simply represent an effector stage that is optimized to cause less inflammation and immunopathology than normal effector T-cells. Such an adjustment in combination with persisting expression of PD-1 could be of vital importance in chronic infections 64,65 . In strong support of this concept, it was recently shown that a high dose virus infection, which induced a strong "exhausted" phenotype, protected mice from immunopathology while a lower dose, which failed to induce an "exhausted" phenotype, resulted in substantial pathology 74,77 .…”