The glycoimmune checkpoint receptor Siglec-7 interacts with T-cell ligands and regulates T-cell activation.
The glycoimmune checkpoint receptor Siglec-7 interacts with T-cell ligands and regulates T-cell activation.
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DOI：
10.1016/j.jbc.2023.105579
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发表时间：
2024-02
影响因子：
4.8
通讯作者：
Wisnovsky, Simon
中科院分区：
文献类型：
--
作者：
Stewart, Natalie;Daly, John;Drummond-Guy, Olivia;Krishnamoorthy, Vignesh;Stark, Jessica C;Riley, Nicholas M;Williams, Karla C;Bertozzi, Carolyn R;Wisnovsky, Simon
Siglec-7(唾液酸结合免疫球蛋白样凝集素7)是一种糖链结合的免疫受体，正在成为癌症免疫治疗的重要靶点。然而，结合Siglec-7的生理配体仍未完全确定。在这项研究中，我们研究了Siglec-7配体在外周免疫细胞亚群上的表达，并评估了Siglec-7是否在功能上调节免疫细胞之间的相互作用。我们发现二唾液酸核10-糖链是Siglec-7的主要免疫配体，并且这些配体在幼稚T细胞上的表达特别高。浓密糖基化的唾液粘蛋白是这些多糖的主要载体，特别是细胞表面标记CD43的糖形式。Siglec-7结合多糖的生物合成是通过涉及糖基转移酶GCNT1的遗传回路在不同的免疫细胞亚群上动态控制的。在体外，Siglec-7阻断被发现同时增加了原始T细胞和抗原提呈树突状细胞的激活，表明Siglec-7结合T细胞糖链调节免疫内信号。最后，我们提出了Siglec-7直接激活T细胞中的信号通路的证据，表明该受体具有新的生物学功能。这些研究最终证明了一个新的Siglec-7介导的信号轴的存在，它在生理上调节T细胞的活动。展望未来，我们的发现对设计和实施针对免疫调节Siglec受体的治疗具有重要意义。
Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is a glycan-binding immune receptor that is emerging as a significant target of interest for cancer immunotherapy. The physiological ligands that bind Siglec-7, however, remain incompletely defined. In this study, we characterized the expression of Siglec-7 ligands on peripheral immune cell subsets and assessed whether Siglec-7 functionally regulates interactions between immune cells. We found that disialyl core 1 O-glycans are the major immune ligands for Siglec-7 and that these ligands are particularly highly expressed on naïve T-cells. Densely glycosylated sialomucins are the primary carriers of these glycans, in particular a glycoform of the cell-surface marker CD43. Biosynthesis of Siglec-7-binding glycans is dynamically controlled on different immune cell subsets through a genetic circuit involving the glycosyltransferase GCNT1. Siglec-7 blockade was found to increase activation of both primary T-cells and antigen-presenting dendritic cells in vitro, indicating that Siglec-7 binds T-cell glycans to regulate intraimmune signaling. Finally, we present evidence that Siglec-7 directly activates signaling pathways in T-cells, suggesting a new biological function for this receptor. These studies conclusively demonstrate the existence of a novel Siglec-7-mediated signaling axis that physiologically regulates T-cell activity. Going forward, our findings have significant implications for the design and implementation of therapies targeting immunoregulatory Siglec receptors.