tailieunhanh - Báo cáo khoa học: Activity of soluble OX40 ligand is enhanced by oligomerization and cell surface immobilization

OX40 ligand (OX40L) and OX40 are typical members of the tumor necrosis factor ligand family and the tumor necrosis factor receptor super-family, respectively, and are involved in the costimulation and differentia-tion of T cells. Like other tumor necrosis factor ligands, OX40L is a type II transmembrane protein. | ễFEBS Journal Activity of soluble OX40 ligand is enhanced by oligomerization and cell surface immobilization Nicole Muller1 Agnes Wyzgol1 Sabine Munkel2 Klaus Pfizenmaier2 and Harald Wajant1 1 Department of Molecular InternalMedicine MedicalClinic and Polyclinic II University of Wuerzburg Germany 2 Institute of Cell Biology and Immunology University of Stuttgart Germany Keywords FAP NF-kB oligomerization OX40L single chain Correspondence H. Wajant Department of Molecular Medicine MedicalClinic and Polyclinic II University of Wuerzburg Roentgenring 11 97070 Wuerzburg Germany Fax 49 931 201 71070 Tel 49 931 201 71010 E-mail These authors contributed equally to this work Received 7 December 2007 revised 25 February 2008 accepted 6 March 2008 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. doi The ligands of the tumor necrosis factor TNF family and their corresponding receptors are crucially involved in a