Genetic and Epigenetic Regulation of PD-1 Expression

Abstract

The inhibitory immune receptor programmed cell death-1 (PD-1) is intricately regulated. In T cells, PD-1 is expressed in response to most immune challenges, but it is rapidly downregulated in acute settings, allowing for normal immune responses. On chronically stimulated Ag-specific T cells, PD-1 expression remains high, leading to an impaired response to stimuli. Ab blockade of PD-1 interactions during chronic Ag settings partially restores immune function and is now used clinically to treat a variety of devastating cancers. Understanding the regulation of PD-1 expression may be useful for developing novel immune-based therapies. In this review, the molecular mechanisms that drive dynamic PD-1 expression during acute and chronic antigenic stimuli are discussed. An array of cis-DNA elements, transcription factors, and epigenetic components, including DNA methylation and histone modifications, control PD-1 expression. The interplay between these regulators fine-tunes PD-1 expression in different inflammatory environments and across numerous cell types to modulate immune responses.

Figure 1. Schematic models of Pdcd1 gene regulation

The Pdcd1 gene is represented in the various activation states (ON, OFF) with (a) major cis-regulatory elements identified relative to the transcription start site (TSS). The positions of two transcriptional insulators (In) that bind CTCF and encompass the locus are represented. Three in vivo transcriptional states representing the activity of the locus in the (a) naïve state and then following (b and c) acute (early and late) and chronic (d) LCMV infections are shown. (e) Ex vivo stimulation of CD8 T cells with cytokines IFNα, IL6, or IL12. (f) Ex vivo and/or in vitro stimulation of macrophages with TLR ligands or IFNα. In each, transcriptional activators/repressors, activating or repressive nucleosomes, and DNA methylation states are depicted as indicated.