Key Points LSD1 suppresses PD-1 expression following acute infection or ex vivo induction. Blimp-1 binding to the Pdcd1 locus is required to recruit LSD1. LSD1 is required to fully remethylate the Pdcd1 proximal promoter region. Visual 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, LSD1-deficient 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.

中文翻译：

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急性感染期间的 PD-1 表达通过 LSD1–Blimp-1 轴受到抑制

关键点 LSD1 在急性感染或离体诱导后抑制 PD-1 表达。需要 Blimp-1 与 Pdcd1 基因座结合才能招募 LSD1。LSD1 需要完全重新甲基化 Pdcd1 近端启动子区域。视觉摘要 在长期暴露于 Ags 期间，例如慢性病毒感染，持续的 TCR 信号可导致 T 细胞耗竭，部分由 Pdcd1 基因编码的程序性细胞死亡-1 (PD-1) 的表达介导。在这项研究中，在 CD8 T 细胞的离体和体内激活过程中，组蛋白 H3K4 修饰在 Pdcd1 基因座上的动态变化表明组蛋白 H3 赖氨酸 4 脱甲基酶 LSD1 在调节 PD-1 表达方面具有潜在作用。缺乏 LSD1 的 CD8 T 细胞在体外刺激后表达更高水平的 Pdcd1 mRNA 以及在急性期增加表面水平的 PD-1，但不是慢性淋巴细胞脉络丛脑膜炎病毒 (LCMV) 感染。Blimp-1 是一种已知的 PD-1 抑制因子，它在急性而非慢性 LCMV 感染期间将 LSD1 募集到 Pdcd1 基因。Pdcd1 近启动子调控区 DNA 甲基化的缺失与其表达高度相关。然而，在急性 LCMV 感染后，PD-1 表达水平恢复到接近基线水平，LSD1 缺陷型 CD8 T 细胞未能将 Pdcd1 基因座重新甲基化至野生型细胞的水平。最后，在鼠黑色素瘤模型中，表达 PD-1 的肿瘤浸润性 LSD1 缺陷型 CD8 T 细胞的频率高于野生型。因此，LSD1 被 Blimp-1 募集到 Pdcd1 基因座，通过促进激活组蛋白标记的去除来下调 PD-1 表达，并且对于基因座的再甲基化很重要。一起，