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Activity of soluble OX40 ligand is enhanced by oligomerization and cell surface immobilization
Author(s) -
Müller Nicole,
Wyzgol Agnes,
Münkel Sabine,
Pfizenmaier Klaus,
Wajant Harald
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2008.06382.x
Subject(s) - ligand (biochemistry) , fusion protein , transmembrane protein , tumor necrosis factor alpha , microbiology and biotechnology , chemistry , antigen , recombinant dna , receptor , biology , biochemistry , immunology , gene
OX40 ligand (OX40L) and OX40 are typical members of the tumor necrosis factor ligand family and the tumor necrosis factor receptor superfamily, respectively, and are involved in the costimulation and differentiation of T cells. Like other tumor necrosis factor ligands, OX40L is a type II transmembrane protein. Recombinant soluble human OX40L assembles into trimers and is practically inactive despite binding to OX40. However, oligomerization of soluble OX40L trimers by cross‐linking with antibodies or by expression as a hexameric fusion protein strongly increased the activity of the ligand. Moreover, a fusion protein of OX40L with a single chain fragment recognizing the tumor stroma antigen fibroblast activation protein showed a cell surface antigen‐dependent increase in the activity of the ligand domain of the molecule and thus mimicked the activity of membrane OX40L upon antigen binding. Trimeric single chain OX40L fusion proteins therefore represent a novel type of OX40L‐derived immunostimulatory molecule with potentially reduced systemic side effects.