PD-1 Expression during Acute Infection Is Repressed through an LSD1–Blimp-1 Axis

Abstract

During prolonged exposure to Ags, such as chronic viral infections, sustained TCR signaling can result in T cell exhaustion mediated in part by expression of programmed cell death-1 (PD-1) encoded by the Pdcd1 gene. In this study, dynamic changes in histone H3K4 modifications at the Pdcd1 locus during ex vivo and in vivo activation of CD8 T cells suggested a potential role for the histone H3 lysine 4 demethylase LSD1 in regulating PD-1 expression. CD8 T cells lacking LSD1 expressed higher levels of Pdcd1 mRNA following ex vivo stimulation as well as increased surface levels of PD-1 during acute, but not chronic, infection with lymphocytic choriomeningitis virus (LCMV). Blimp-1, a known repressor of PD-1, recruited LSD1 to the Pdcd1 gene during acute, but not chronic, LCMV infection. Loss of DNA methylation at Pdcd1's promoter-proximal regulatory regions is highly correlated with its expression. However, following acute LCMV infection, in which PD-1 expression levels return to near baseline, LSD1deficient CD8 T cells failed to remethylate the Pdcd1 locus to the levels of wild-type cells. Finally, in a murine melanoma model, the frequency of PD-1-expressing tumor-infiltrating LSD1-deficient CD8 T cells was greater than in wild type. Thus, LSD1 is recruited to the Pdcd1 locus by Blimp-1, downregulates PD-1 expression by facilitating the removal of activating histone marks, and is important for remethylation of the locus. Together, these data provide insight into the complex regulatory mechanisms governing T cell immunity and regulation of a critical T cell checkpoint gene.

Inhibitory Molecules PD-1, CD73 and CD39 Are Expressed by CD8+ T Cells in a Tissue-Dependent Manner and Can Inhibit T Cell Responses to Stimulation

“…Collectively, these data are striking since PD-1 is well-described to be silenced in the absence of ongoing antigen stimulation. Repression of PD-1 is induced by the B-lymphocyte-induced maturation protein-1 (Blimp-1), which alters transcription factor binding in the pdcd1 (PD-1) gene promoter and promotes repressive histone methylation (71,72) unless T cells are exposed to chronic antigen (73,74). Thus, together these data imply that repression of PD-1 fails to occur in some non-lymphoid tissues and it will be interesting to determine whether the repressive methylation of the pdcd1 promoter is impaired in salivary gland or kidney-localized T cells, or T cells in other tissues.…”

Identification of a Sensitive Human Immunological Target of Aryl Hydrocarbon Receptor Activation: CD5+ Innate-Like B Cells

“…This could be explained, in part by AHR binding with the RelA subunit, which would have negative overall effects on NF-kB activation while facilitating increased expression of PD-1 (65)(66)(67). Alternatively, a recent report by Bally and colleagues suggested that the lysine-specific histone demethylase 1 (LSD1) protein was recruited by B lymphocyte-induced maturation protein-1 (BLIMP-1) to repress transcription of PD-1 by binding to the PD-1 promoter region (68). This was confirmed by the finding that in LSD1 deficient mice, CD8 + T cells expressed elevated levels of PD-1 (68).…”

“…Alternatively, a recent report by Bally and colleagues suggested that the lysine-specific histone demethylase 1 (LSD1) protein was recruited by B lymphocyte-induced maturation protein-1 (BLIMP-1) to repress transcription of PD-1 by binding to the PD-1 promoter region (68). This was confirmed by the finding that in LSD1 deficient mice, CD8 + T cells expressed elevated levels of PD-1 (68). It is well known that TCDD-mediated AHR activation significantly suppresses BLIMP-1 expression in human B cells (1).…”

Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

“…PD-1 expression in T cells is known to be upregulated following TCR-mediated activation [60,61]. A previous study demonstrated that the common γ-chain cytokines including IL-2 and IL-15, which could be produced by myeloid cells and B cells, also upregulate PD-1 expression in T cells [60].…”