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Galectin-3 Decreases 4-1BBL Bioactivity by Crosslinking Soluble and Membrane Expressed 4-1BB

Nielsen, Morten Aagaard ; Juul-Madsen, Kristian ; Stegmayr, John LU ; Gao, Chao ; Mehta, Akul Y. ; Greisen, Stinne Ravn ; Kragstrup, Tue Wenzel ; Hvid, Malene ; Vorup-Jensen, Thomas and Cummings, Richard D. , et al. (2022) In Frontiers in Immunology 13.
Abstract

4-1BB is a T cell costimulatory receptor and a member of the tumor necrosis factor receptor superfamily. Here, we show that Galectin-3 (Gal-3) decreases the cellular response to its ligand (4-1BBL). Gal-3 binds to both soluble 4-1BB (s4-1BB) and membrane-bound 4-1BB (mem4-1BB), without blocking co-binding of 4-1BBL. In plasma, we detected complexes composed of 4-1BB and Gal-3 larger than 100 nm in size; these complexes were reduced in synovial fluid from rheumatoid arthritis. Both activated 4-1BB+ T cells and 4-1BB-transfected HEK293 cells depleted these complexes from plasma, followed by increased expression of 4-1BB and Gal-3 on the cell surface. The increase was accompanied by a 4-fold decrease in TNFα production by the... (More)

4-1BB is a T cell costimulatory receptor and a member of the tumor necrosis factor receptor superfamily. Here, we show that Galectin-3 (Gal-3) decreases the cellular response to its ligand (4-1BBL). Gal-3 binds to both soluble 4-1BB (s4-1BB) and membrane-bound 4-1BB (mem4-1BB), without blocking co-binding of 4-1BBL. In plasma, we detected complexes composed of 4-1BB and Gal-3 larger than 100 nm in size; these complexes were reduced in synovial fluid from rheumatoid arthritis. Both activated 4-1BB+ T cells and 4-1BB-transfected HEK293 cells depleted these complexes from plasma, followed by increased expression of 4-1BB and Gal-3 on the cell surface. The increase was accompanied by a 4-fold decrease in TNFα production by the 4-1BBhighGal-3+ T cells, after exposure to 4-1BB/Gal-3 complexes. In RA patients, complexes containing 4-1BB/Gal-3 were dramatically reduced in both plasma and SF compared with healthy plasma. These results support that Gal-3 binds to 4-1BB without blocking the co-binding of 4-1BBL. Instead, Gal-3 leads to formation of large soluble 4-1BB/Gal-3 complexes that attach to mem4-1BB on the cell surfaces, resulting in suppression of 4-1BBL’s bioactivity.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
4-1BB, checkpoint receptor, Galectin-3, inflammation, rheumatoid arthritis
in
Frontiers in Immunology
volume
13
article number
915890
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85134067706
  • pmid:35812455
ISSN
1664-3224
DOI
10.3389/fimmu.2022.915890
language
English
LU publication?
yes
id
e17c4fa6-4098-4455-818e-3ad056a46f95
date added to LUP
2022-10-06 09:23:13
date last changed
2024-06-13 19:53:24
@article{e17c4fa6-4098-4455-818e-3ad056a46f95,
  abstract     = {{<p>4-1BB is a T cell costimulatory receptor and a member of the tumor necrosis factor receptor superfamily. Here, we show that Galectin-3 (Gal-3) decreases the cellular response to its ligand (4-1BBL). Gal-3 binds to both soluble 4-1BB (s4-1BB) and membrane-bound 4-1BB (mem4-1BB), without blocking co-binding of 4-1BBL. In plasma, we detected complexes composed of 4-1BB and Gal-3 larger than 100 nm in size; these complexes were reduced in synovial fluid from rheumatoid arthritis. Both activated 4-1BB<sup>+</sup> T cells and 4-1BB-transfected HEK293 cells depleted these complexes from plasma, followed by increased expression of 4-1BB and Gal-3 on the cell surface. The increase was accompanied by a 4-fold decrease in TNFα production by the 4-1BB<sup>high</sup>Gal-3<sup>+</sup> T cells, after exposure to 4-1BB/Gal-3 complexes. In RA patients, complexes containing 4-1BB/Gal-3 were dramatically reduced in both plasma and SF compared with healthy plasma. These results support that Gal-3 binds to 4-1BB without blocking the co-binding of 4-1BBL. Instead, Gal-3 leads to formation of large soluble 4-1BB/Gal-3 complexes that attach to mem4-1BB on the cell surfaces, resulting in suppression of 4-1BBL’s bioactivity.</p>}},
  author       = {{Nielsen, Morten Aagaard and Juul-Madsen, Kristian and Stegmayr, John and Gao, Chao and Mehta, Akul Y. and Greisen, Stinne Ravn and Kragstrup, Tue Wenzel and Hvid, Malene and Vorup-Jensen, Thomas and Cummings, Richard D. and Leffler, Hakon and Deleuran, Bent Winding}},
  issn         = {{1664-3224}},
  keywords     = {{4-1BB; checkpoint receptor; Galectin-3; inflammation; rheumatoid arthritis}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Galectin-3 Decreases 4-1BBL Bioactivity by Crosslinking Soluble and Membrane Expressed 4-1BB}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.915890}},
  doi          = {{10.3389/fimmu.2022.915890}},
  volume       = {{13}},
  year         = {{2022}},
}