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

Mei Tzu Su, Masanori Inui, Yi Li Wong, Maika Takahashi, Akiko Sugahara-Tobinai, Karin Ono, Shotaro Miyamoto, Keiichi Murakami, Ari Itoh-Nakadai, Dai Kezuka, So Itoi, Shota Endo, Kouyuki Hirayasu, Hisashi Arase, Toshiyuki Takai

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)447-458
Number of pages12
JournalInternational immunology
Volume33
Issue number8
DOIs
Publication statusPublished - 2021 Aug 1

Keywords

  • auto-antibody
  • B-cell development
  • immune checkpoint
  • systemic lupus erythematosus
  • tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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