LSD1 regulates PD-1 expression through interactions with Blimp-1 during acute viral infection

Abstract

Abstract During prolonged exposure to antigens, such as during chronic viral infections, sustained T cell receptor (TCR) signaling via cognate peptide: MHC interactions results in T cell exhaustion mediated in part by the expression of Programmed cell death protein 1 (PD-1). PD-1 blockade has been implemented in the clinical setting as a promising treatment for several different forms of cancer and therefore obtaining a complete understanding of the epigenetic mechanisms that regulate PD-1 is of great value to improving existing therapies. Here, we demonstrate that CD8 positive T cells lacking lysine-specific histone demethylase 1A (LSD1) expressed approximately 2-fold higher levels of PD-1 mRNA following TCR stimulation. Antigen specific CD8 T cells lacking LSD1 also showed increased surface levels of PD-1 during acute infection with LCMV but not during chronic infection. Molecular analysis revealed that Blimp-1, a known repressor of PD-1, recruits LSD1 for silencing. Although Blimp-1 is able to bind the PD-1 locus during both acute and chronic LCMV infection, it fails to recruit LSD1 in the chronic setting. LSD1 is responsible for removing activating histone modifications H3K4me1 and H3K4me2 and our results show that these marks are removed from the PD-1 locus only during acute infection. During viral infection, loss of DNA methylation is associated with with PD-1 expression. Examination of the PD-1 locus during acute infection revealed that LSD1 null CD8 T cells had less methylation compared to cells expressing LSD1 further demonstrating the role of LSD1 in regulating PD-1 expression. Taken together, these results demonstrate LSD1 downregulates PD-1 by interactions with Blimp-1.