Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice

• Published in: International immunology Vol. 33; no. 8; pp. 447 - 458
• Main Authors: Su, Mei-Tzu, Inui, Masanori, Wong, Yi Li, Takahashi, Maika, Sugahara-Tobinai, Akiko, Ono, Karin, Miyamoto, Shotaro, Murakami, Keiichi, Itoh-Nakadai, Ari, Kezuka, Dai, Itoi, So, Endo, Shota, Hirayasu, Kouyuki, Arase, Hisashi, Takai, Toshiyuki
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 01.08.2021
• Subjects: Animals; Autoimmune Diseases - immunology; Autoimmune Diseases - metabolism; Autoimmunity - immunology; Cell Communication - immunology; Cell Line, Tumor; Cells, Cultured; Fibronectins - immunology; Fibronectins - metabolism; Human Umbilical Vein Endothelial Cells - immunology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mice; Phagocytosis - immunology; RAW 264.7 Cells; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; THP-1 Cells - immunology; THP-1 Cells - metabolism; B-cell development; systemic lupus erythematosus; auto-antibody; tolerance; immune checkpoint
• ISSN: 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxab028

Abstract 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. Fibronectin functions as an immune checkpoint molecule