2024年9月17日，美国博德研究所Debattama R. Sen等研究人员在《自然—免疫学》杂志发表论文，发现PD-1表达的表观遗传调节可改善衰竭T细胞功能和病毒控制。

研究人员使用小鼠模型功能性地探讨了PD-1的表观遗传调控，并删除了衰竭特异性PD-1增强子。增强子的删除仅改变慢性感染中CD8⁺ T细胞的PD-1表达，形成了一个中间表达的“甜蜜点”，在此状态下T细胞功能相比野生型和Pdcd1敲除细胞得到优化。这使得在不增加免疫病理的情况下更好地控制慢性感染。

综合这些结果表明，通过表观遗传编辑调节PD-1可以减少CD8⁺ T细胞功能障碍，同时避免过度的免疫病理。

据悉，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，衰竭T细胞高度表达PD-1。虽然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并促进记忆形成。驱动衰竭状态下高PD-1表达的机制尚不完全清楚，理解这些机制对于区分其有益和有害影响至关重要。

附：英文原文

Title: Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control

Author: Weiss, Sarah A., Huang, Amy Y., Fung, Megan E., Martinez, Daniela, Chen, Alex C. Y., LaSalle, Thomas J., Miller, Brian C., Scharer, Christopher D., Hegde, Mudra, Nguyen, Thao H., Rowe, Jared H., Osborn, Jossef F., Patterson, Dillon G., Sifnugel, Natalia, Mei-An Nolan, C., Davidson, Richard A., Schwartz, Marc A., Bally, Alexander P. R., Neeld, Dennis K., LaFleur, Martin W., Boss, Jeremy M., Doench, John G., Nicholas Haining, W., Sharpe, Arlene H., Sen, Debattama R.

Issue&Volume: 2024-09-17

Abstract: 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.

DOI: 10.1038/s41590-024-01961-3

Source: https://www.nature.com/articles/s41590-024-01961-3