TY - JOUR
T1 - Galectin-3 Decreases 4-1BBL Bioactivity by Crosslinking Soluble and Membrane Expressed 4-1BB
AU - Nielsen, Morten Aagaard
AU - Juul-Madsen, Kristian
AU - Stegmayr, John
AU - Gao, Chao
AU - Mehta, Akul Y.
AU - Greisen, Stinne Ravn
AU - Kragstrup, Tue Wenzel
AU - Hvid, Malene
AU - Vorup-Jensen, Thomas
AU - Cummings, Richard D.
AU - Leffler, Hakon
AU - Deleuran, Bent Winding
N1 - Publisher Copyright:
Copyright © 2022 Nielsen, Juul-Madsen, Stegmayr, Gao, Mehta, Greisen, Kragstrup, Hvid, Vorup-Jensen, Cummings, Leffler and Deleuran.
PY - 2022/6/24
Y1 - 2022/6/24
N2 - 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.
AB - 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.
KW - 4-1BB
KW - checkpoint receptor
KW - Galectin-3
KW - inflammation
KW - rheumatoid arthritis
UR - http://www.scopus.com/inward/record.url?scp=85134067706&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2022.915890
DO - 10.3389/fimmu.2022.915890
M3 - Journal article
C2 - 35812455
AN - SCOPUS:85134067706
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 915890
ER -