PD-1 is negatively regulated by LSD1 through interactions with Blimp-1 during acute viral infection

Abstract

Abstract Prolonged exposure to antigen, such as during chronic viral infections and cancer, leads to sustained TCR signaling and ultimately T cell exhaustion, which is in part mediated by up regulation of Programmed cell death 1 (PD-1). Antibody blockade of PD-1 does not work in all instances and can lead to autoimmunity, thus identifying novel tools to manipulate PD-1 are needed. Therefore, we sought to understand the genetic and epigenetic mechanisms that regulate PD-1 during acute and chronic antigen conditions in order to identify additional therapeutic targets to modulate PD-1. We determined the chromatin status at the PD-1 locus and found that activating H3K4me1 and H3K4me2 epigenetic modifications were still present at day 8 during a chronic but not acute LCMV infection. This suggested a failure to remove the active histone marks in chronic infections. Indeed, CD8 T cells lacking lysine-specific histone demethylase 1A (LSD1), a H3K4 demethylase, display significantly higher levels of PD-1 mRNA and protein during acute but not chronic infection. Molecular analysis revealed that Blimp-1 recruits LSD1 to the PD-1 locus to induce silencing during acute infection. Despite Blimp-1 binding to the PD-1 locus during both acute and chronic LCMV infection, it fails to recruit LSD1 during the chronic setting. Additionally, failure to remove H3K4 methylation resulted in less DNA methylation at known PD-1 control regions compared to wild-type cells, consistent with the differential expression of PD-1. Taken together, these results demonstrate that LSD1 downregulates PD-1 by interacting with Blimp-1 during acute, but not chronic LCMV infection, facilitating full epigenetic repression of the locus.