Galectin-3 interacts with PD-1 and counteracts the PD-1 pathway-driven regulation of T cell and osteoclast activity in Rheumatoid Arthritis

Scand J Immunol. 2023 Feb;97(2):e13245. doi: 10.1111/sji.13245. Epub 2022 Dec 30.


Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and bone erosions. The glycosylated programmed death-1 (PD-1) receptor plays an important role in regulating immune responses and maintaining tolerance. In this study, we focus on two features observed in RA: impaired PD-1 signalling and Galectin-3 (Gal-3) upregulation. We hypothesize that Gal-3 binds PD-1 and PD-1 ligands, potentially contributing to impaired PD-1 signalling. PD-1 and Gal-3 levels in RA synovial fluid (SF) and plasma were evaluated by ELISA. PD-1 and Gal-3 interaction was examined by Surface Plasmon Resonance and ELISA. PD-1, PD-L1 and Gal-3 expression on mononuclear cells from SF and peripheral blood as well as fibroblast-like synoviocytes were examined by flow cytometry. Effects of Gal-3 and PD-L1 on osteoclast formation was evaluated by tartrate-resistant acid phosphatase assay. We show that Gal-3 binds PD-1 and PD-L1. Results demonstrated high expression of PD-1 and Gal-3 on mononuclear cells, especially from SF. Gal-3 inhibited PD-1 signalling when PD-L1 was present. Furthermore, a role of Gal-3 in osteoclast formation was observed in vitro, both directly but also through PD-1:PD-L1 inhibition. Effects of Gal-3 on the PD-1 signalling axis are proposed to be inhibitory, meaning high Gal-3 levels in the complex synovial microenvironment are not desirable in RA. Preventing Gal-3's inhibitory role on PD-1 signalling could, therefore, be a therapeutic target in RA by affecting inflammatory T cell responses and osteoclasts.

Keywords: Galectin-3; PD-1; autoimmunity; co-inhibitory receptors; inflammation; rheumatoid arthritis.

MeSH terms

  • Arthritis, Rheumatoid* / metabolism
  • Arthritis, Rheumatoid* / pathology
  • B7-H1 Antigen / metabolism
  • Galectin 3* / metabolism
  • Humans
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Programmed Cell Death 1 Receptor* / metabolism
  • T-Lymphocytes* / metabolism
  • T-Lymphocytes* / pathology


  • B7-H1 Antigen
  • Galectin 3
  • Programmed Cell Death 1 Receptor