PD-1 is a key negative regulator of CD8⁺ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8⁺ T cells in chronic infection, creating a ‘sweet spot’ of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8⁺ T cell dysfunction while avoiding excess immunopathology.

PD-1 是 CD8⁺ T 细胞活化的关键负调节因子，在癌症和慢性病毒感染中由耗竭的 T 细胞高度表达。尽管 PD-1 阻断可以改善病毒和肿瘤控制，但生理性 PD-1 表达可防止免疫病理学并改善记忆形成。在耗竭中驱动 PD-1 高表达的机制尚不清楚，对于理清其有益和有害的影响可能至关重要。在这里，我们使用删除耗竭特异性 PD-1 增强子的小鼠模型对 PD-1 的表观遗传调控进行了功能研究。在慢性感染中，增强子缺失仅改变 CD8⁺ T 细胞中的 PD-1 表达，从而产生中间表达的“最佳位置”，与野生型和 Pdcd1 敲除细胞相比，T 细胞功能得到优化。这允许在没有额外免疫病理学的情况下改善对慢性感染的控制。总之，这些结果表明，通过表观遗传编辑调整 PD-1 可以减少 CD8⁺ T 细胞功能障碍，同时避免过度免疫病理学。