Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice.
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.
['Su|Mei-Tzu|MT|', 'Inui|Masanori|M|', 'Wong|Yi Li|YL|', 'Takahashi|Maika|M|', 'Sugahara-Tobinai|Akiko|A|', 'Ono|Karin|K|', 'Miyamoto|Shotaro|S|', 'Murakami|Keiichi|K|', 'Itoh-Nakadai|Ari|A|', 'Kezuka|Dai|D|', 'Itoi|So|S|', 'Endo|Shota|S|', 'Hirayasu|Kouyuki|K|', 'Arase|Hisashi|H|0000-0002-1153-3166', 'Takai|Toshiyuki|T|0000-0002-4549-7116']
immune checkpoint B-cell development auto-antibody systemic lupus erythematosus tolerance