期刊
ACS NANO
卷 15, 期 2, 页码 3441-3452出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.0c10632
关键词
DNA nanotechnology; DNA origami; PD-1 receptor; cancer immunotherapy; nanoscale spatial distribution
类别
资金
- European Research Council under the European Union [617711]
- Swedish Research Council [2015-03520]
- Knut and Alice Wallenberg Foundation [KAW 2017.0114]
- Strategic Research Area (SFO) program of the Swedish Research Council
- Swedish Foundation for Strategic Research [FFL15-0031]
- Swedish Research Council [2015-03520] Funding Source: Swedish Research Council
- Swedish Foundation for Strategic Research (SSF) [FFL15-0031] Funding Source: Swedish Foundation for Strategic Research (SSF)
- European Research Council (ERC) [617711] Funding Source: European Research Council (ERC)
The spatial organization of PD-L1 plays a crucial role in regulating T-cell signaling, with PD-L1 ligands at 200 nm distance being more effective in inhibiting T-cell activation and reducing IL-2 expression compared to closer distances. These findings may guide the development of nanomedicine-based immunomodulatory therapies in the future.
Programmed Death-1 (PD-1) is a coinhibitory receptor expressed on activated T cells that suppresses T-cell signaling and effector functions. It has been previously shown that binding to its ligand PD-L1 induces a spatial reorganization of PD-1 receptors into microclusters on the cell membrane. However, the roles of the spatial organization of PD-L1 on PD-1 clustering and T-cell signaling have not been elucidated. Here, we used DNA origami flat sheets to display PD-L1 ligands at defined nanoscale distances and investigated their ability to inhibit T-cell activation in vitro. We found that DNA origami flat sheets modified with CD3 and CD28 activating antibodies (FS-alpha-CD3-CD28) induced robust T-cell activation. Co-treatment with flat sheets presenting PD-L1 ligands separated by similar to 200 nm (FS-PD-L1-200), but not 13 nm (FS-PD-L1-13) or 40 nm (FS-PD-L1-40), caused an inhibition of T-cell signaling, which increased with increasing molar ratio of FS-PD-L1-200 to FS-alpha-CD3-CD28. Furthermore, FS-PD-L1-200 induced the formation of smaller PD-1 nanoclusters and caused a larger reduction in IL-2 expression compared to FS-PD-L1-13. Together, these findings suggest that the spatial organization of PD-L1 determines its ability to regulate T-cell signaling and may guide the development of future nanomedicine-based immunomodulatory therapies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据