Transcriptional and epigenetic regulation of PD-1 expression

Abstract

Programmed cell death-1 (PD-1) is a co-inhibitory receptor that plays important roles in regulating T cell immunity and peripheral tolerance. PD-1 signaling prevents T cells from overactivation during acute infections, but it maintains T cell exhaustion during chronic infections. Tumor cells can exploit the PD-1 signaling pathway to evade antitumor immune responses. The PD-1 signaling pathway is also essential for maintaining peripheral tolerance and prevention of autoimmunity. PD-1 expression is strictly and differentially regulated by diverse mechanisms in immune cells. It is activated and repressed by distinct transcription factors in different circumstances. Moreover, epigenetic mechanisms are also involved in regulating PD-1 expression. In this review, we summarize the knowledge of the transcriptional and epigenetic regulation of PD-1 expression during different immune responses.

Keywords: Epigenetic regulation; Gene expression; PD-1; Transcriptional regulation.

Fig. 1

Suppression of T cell responses by the PD-1 signaling pathway. When PD-1 is engaged with its ligand, PD-L1 or PD-L2 on antigen-presenting cells (APC), it becomes phosphorylated at the tyrosine residues of the ITIM and ITSM in its intracellular domain. PD-1 then recruits the protein tyrosine phosphatase SHP-2 to its ITSM. SHP-2 can inhibit the signaling events triggered by TCR (interacting with the peptide-MHC complex) and CD28 (interacting with CD80 or CD86) via dephosphorylating the kinases ZAP70, PI3K, and Ras. This results in decreased activation of transcription factors such as AP-1, NFAT, and NF-κB, which are important for T cell activation, proliferation, effector functions and survival

Fig. 2

Cancer immunotherapies via antibody blockade of the PD-1 signaling pathway. a Signaling through the interaction of PD-1 on tumor-infiltrating T cells with PD-L1 on tumor cells makes tumor-infiltrating T cells exhausted, thus tumor cells can evade host immune attack. b Blockade of the PD-1 signaling pathway via an anti-PD-1 antibody reinvigorates exhausted tumor-infiltrating T cells. Tumor-infiltrating T cells then restore the effector functions to kill tumor cells