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

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.

Juul-Madsen, KristianAarhus University (author)
Stegmayr, JohnLund University,Lunds universitet,Lungbioengineering och regeneration,Forskargrupper vid Lunds universitet,LTH profilområde: Nanovetenskap och halvledarteknologi,LTH profilområden,Lunds Tekniska Högskola,Lung Bioengineering and Regeneration,Lund University Research Groups,LTH Profile Area: Nanoscience and Semiconductor Technology,LTH Profile areas,Faculty of Engineering, LTH(Swepub:lu)cob-jns (author)
Gao, ChaoHarvard Medical School (author)
Mehta, Akul Y.Harvard Medical School (author)
Greisen, Stinne RavnAarhus University,Aarhus University Hospital (author)
Kragstrup, Tue WenzelAarhus University,Aarhus University Hospital (author)
Hvid, MaleneAarhus University (author)
Vorup-Jensen, ThomasAarhus University (author)
Cummings, Richard D.Harvard Medical School (author)
Leffler, HakonLund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)mmb-hle (author)
Deleuran, Bent WindingAarhus University Hospital,Aarhus University (author)
Aarhus University HospitalAarhus University (creator_code:org_t)

By the author/editor: Nielsen, Morten ...; Juul-Madsen, Kri ...; Stegmayr, John; Gao, Chao; Mehta, Akul Y.; Greisen, Stinne ...; show more...; Kragstrup, Tue W ...; Hvid, Malene; Vorup-Jensen, Th ...; Cummings, Richar ...; Leffler, Hakon; Deleuran, Bent W ...; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Cell Biology

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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