The extracellular matrix (ECM) is the basis for virtually all cellular processes and is also related to tumor metastasis. Fibronectin (FN), a major ECM macromolecule expressed by different cell types and also present in plasma, consists of multiple functional modules that bind to ECM-associated, plasma, and cell-surface proteins such as integrins and FN itself, thus ensuring its cell-adhesive and modulatory role. Here we show that FN constitutes an immune checkpoint. Thus, FN was identified as a physiological ligand for a tumor/leukemia/lymphoma- as well as autoimmune-associated checkpoint, ILT3/LILRB4 (B4, CD85k). Human B4 and the murine ortholog, gp49B, bound FN with sub-micromolar affinities as assessed by bio-layer interferometry. The major B4-binding site in FN was located at the N-terminal 30-kDa module (FN30), which is apart from the major integrin-binding site present at the middle of the molecule. Blockade of B4–FN binding such as with B4 antibodies or a recombinant FN30-Fc fusion protein paradoxically ameliorated autoimmune disease in lupus-prone BXSB/Yaa mice. The unexpected nature of the B4–FN checkpoint in autoimmunity is discussed, referring to its potential role in tumor immunity.

中文翻译：

---

阻断检查点 ILT3/LILRB4/gp49B 与纤连蛋白结合可改善 BXSB/Yaa 小鼠的自身免疫性疾病

细胞外基质 (ECM) 是几乎所有细胞过程的基础，也与肿瘤转移有关。纤连蛋白 (FN) 是一种主要的 ECM 大分子，由不同细胞类型表达，也存在于血浆中，由多个功能模块组成，这些模块与 ECM 相关蛋白、血浆和细胞表面蛋白（如整联蛋白和 FN 本身）结合，从而确保其细胞- 粘合和调节作用。在这里，我们表明 FN 构成了一个免疫检查点。因此，FN 被鉴定为肿瘤/白血病/淋巴瘤以及自身免疫相关检查点 ILT3/LILRB4 (B4, CD85k) 的生理配体。人 B4 和鼠类直系同源物 gp49B 通过生物层干涉测量法以亚微摩尔亲和力结合 FN。FN 中的主要 B4 结合位点位于 N 端 30-kDa 模块 (FN30)，除了存在于分子中间的主要整合素结合位点之外。阻断 B4-FN 结合，例如用 B4 抗体或重组 FN30-Fc 融合蛋白反常地改善狼疮易发 BXSB 中的自身免疫性疾病/呀老鼠。讨论了 B4-FN 检查点在自身免疫中的意外性质，指的是其在肿瘤免疫中的潜在作用。