<br>剖析 Siglecs 拮抗 Fcγ 受体的能力,ACS Central Science

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剖析 Siglecs 拮抗 Fcγ 受体的能力
ACS Central Science ( IF 12.7 ) Pub Date : 2024-01-17 , DOI: 10.1021/acscentsci.3c00969
Kelli A McCord ₁ , Chao Wang ₂ , Mirjam Anhalt ₁ , Wayne W Poon ₃ , Amanda L Gavin ₄ , Peng Wu ₂ , Matthew S Macauley _{1,

5}

Affiliation

Fcγ 受体 (FcγR) 在 IgG 的效应器功能中发挥关键作用，但它们的不当激活在多种疾病病因中发挥着重要作用。因此，更好地了解 FcγR 的调控机制至关重要。大量研究表明，唾液酸结合免疫球蛋白型凝集素（Siglecs）是免疫调节受体家族，可调节 FcγR 活性；然而，目前还不清楚Siglecs在什么情况下可以拮抗FcγRs以及哪些Siglecs具有这种能力。使用显示选择性配体的脂质体将 FcγR 与特定的 Siglec 共同接合，我们探索了 Siglec-3、Siglec-5、Siglec-7 和 Siglec-9 拮抗 FcγR 下游信号传导的能力。我们证明，当 Siglec-3 和 Siglec-9 与 FcγR 共同作用时，可以完全抑制 U937 细胞中 FcγR 的激活。表达 Siglec 突变体的细胞揭示了免疫调节酪氨酸抑制基序 (ITIM) 和免疫调节酪氨酸开关基序 (ITSM) 在这种抑制中的不同作用。成像流式细胞术能够以依赖于 ITIM 的方式可视化 SHP-1 招募到 Siglec-3 的情况，而 SHP-2 招募则更依赖于 ITSM。相反，Siglec-9 的两个胞质基序都有助于 SHP-1/2 的招募。 Siglec-7 拮抗 FcγR 激活的能力较差，原因有两个：顺式配体的掩蔽以及 ITIM 和 ITSM 的差异。 Siglec-3 胞外结构域和 Siglec-5 胞质尾部的嵌合体在共同接合时强烈抑制 FcγR，这提供了 Siglec-5 在拮抗 FcγR 能力方面更像 Siglec-3 和 Siglec-9 的证据。此外，当 Siglec-3 和 Siglec-9 与同时显示 Siglec 和 FcγR 配体的细胞共同接合时，Siglec-3 和 Siglec-9 会抑制 FcγR。这些结果表明 Siglecs 在介导免疫突触背景下的 FcγR 抑制中发挥作用，这与免疫疗法的有效性具有重要相关性。

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Dissecting the Ability of Siglecs To Antagonize Fcγ Receptors

Fcγ receptors (FcγRs) play key roles in the effector function of IgG, but their inappropriate activation plays a role in several disease etiologies. Therefore, it is critical to better understand how FcγRs are regulated. Numerous studies suggest that sialic acid-binding immunoglobulin-type lectins (Siglecs), a family of immunomodulatory receptors, modulate FcγR activity; however, it is unclear of the circumstances in which Siglecs can antagonize FcγRs and which Siglecs have this ability. Using liposomes displaying selective ligands to coengage FcγRs with a specific Siglec, we explore the ability of Siglec-3, Siglec-5, Siglec-7, and Siglec-9 to antagonize signaling downstream of FcγRs. We demonstrate that Siglec-3 and Siglec-9 can fully inhibit FcγR activation in U937 cells when coengaged with FcγRs. Cells expressing Siglec mutants reveal differential roles for the immunomodulatory tyrosine-based inhibitory motif (ITIM) and immunomodulatory tyrosine-based switch motif (ITSM) in this inhibition. Imaging flow cytometry enabled visualization of SHP-1 recruitment to Siglec-3 in an ITIM-dependent manner, while SHP-2 recruitment is more ITSM-dependent. Conversely, both cytosolic motifs of Siglec-9 contribute to SHP-1/2 recruitment. Siglec-7 poorly antagonizes FcγR activation for two reasons: masking by cis ligands and differences in its ITIM and ITSM. A chimera of the Siglec-3 extracellular domains and Siglec-5 cytosolic tail strongly inhibits FcγR when coengaged, providing evidence that Siglec-5 is more like Siglec-3 and Siglec-9 in its ability to antagonize FcγRs. Additionally, Siglec-3 and Siglec-9 inhibited FcγRs when coengaged by cells displaying ligands for both the Siglec and FcγRs. These results suggest a role for Siglecs in mediating FcγR inhibition in the context of an immunological synapse, which has important relevance to the effectiveness of immunotherapies.

更新日期：2024-01-17

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