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

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Sustained T cell receptor (TCR) signaling during chronic infections can lead to T cell exhaustion, partly via programmed cell death-1 (PD-1) expression.
• The epigenetic regulation of PD-1 (encoded by the Pdcd1 gene) in CD8 T cells is not fully understood.

Purpose of the Study:

• To investigate the role of histone H3 lysine 4 (H3K4) demethylase LSD1 in regulating PD-1 expression during CD8 T cell activation and exhaustion.
• To elucidate the mechanisms by which LSD1 controls Pdcd1 gene expression.

Main Methods:

• Analysis of histone H3K4 modifications at the Pdcd1 locus in activated CD8 T cells.
• Assessment of PD-1 mRNA and surface protein levels in wild-type and LSD1-deficient CD8 T cells during viral infections (LCMV) and in a melanoma model.
• Investigation of Blimp-1 recruitment of LSD1 to the Pdcd1 gene.
• Analysis of DNA methylation status at the Pdcd1 locus.

Main Results:

• LSD1 deficiency led to increased Pdcd1 mRNA and PD-1 surface levels in CD8 T cells during acute LCMV infection.
• Blimp-1 recruited LSD1 to the Pdcd1 gene during acute LCMV infection, facilitating PD-1 downregulation.
• LSD1-deficient cells showed impaired remethylation of the Pdcd1 locus after acute infection.
• Increased PD-1 expression was observed on tumor-infiltrating LSD1-deficient CD8 T cells in a murine melanoma model.

Conclusions:

• LSD1, recruited by Blimp-1, downregulates PD-1 expression by removing activating histone marks and is crucial for locus remethylation.
• LSD1 plays a significant role in regulating T cell exhaustion and PD-1 expression, impacting anti-tumor immunity.