Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa 920-8640, Japan.
Int Immunol. 2021 Jul 23;33(8):447-458. doi: 10.1093/intimm/dxab028.
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.
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，不同类型的细胞都会表达，也存在于血浆中，它由多个功能模块组成，这些功能模块与 ECM 相关蛋白、血浆蛋白和细胞表面蛋白（如整合素和 FN 自身）结合，从而确保其具有细胞黏附性和调节作用。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。通过生物层干涉测量法评估，人 B4 和鼠同源物 gp49B 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 30kDa 模块 (FN30)，该位点与分子中部的主要整合素结合位点分开。B4 抗体或重组 FN30-Fc 融合蛋白阻断 B4-FN 结合，例如在狼疮易感 BXSB/Yaa 小鼠中反而改善了自身免疫性疾病。讨论了 B4-FN 检查点在自身免疫中的意外性质，涉及它在肿瘤免疫中的潜在作用。
