title: GMP-140 (P-selectin/CD62) binds to chronically stimulated but not resting CD4+ T lymphocytes and regulates their production of proinflammatory cytokines.
abstract: GMP-140 (P-selectin), a 140-kDa granular membrane glycoprotein localized to the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells, is thought to play an important role in adhesive interactions predominantly between granulocytes, platelets and vascular endothelial cells during inflammation. Although GMP-140 binds to granulocytes, its binding to lymphocytes has not been demonstrated. Using genetically engineered IgG C gamma 1 fusion protein of the extracellular domains of GMP-140, we demonstrate that GMP-140 binds to chronically antigen (Ag)-stimulated CD4+ T cells. Freshly isolated CD4+ T cells did not bind GMP-140, but priming and subsequent stimulation with alloantigen induced and gradually increased expression of GMP-140-reactive structures on their surface. T cells isolated from rheumatoid synovial fluids also exhibited strong binding to GMP-140. The binding of GMP-140 to primed T cells is not influenced by preactivation with phorbol 12-myristate 13-acetate, is almost completely abolished by pretreatment of T cells with neuraminidase or trypsin, and is also strongly inhibited by EDTA, the soluble sulfated glycans dextran sulfate, fucoidan, and heparin, but not by chondroitin sulfates. In spite of its strong binding to Ag-primed T cells, GMP-140 did not modulate the proliferative responses of these cells to various stimuli. However, GMP-140 in conjunction with anti-T cell receptor alpha beta monoclonal antibodies augmented the production of granulocyte-macrophage colony-stimulating factor GM-CSF and inhibited the production of interleukin-8 by Ag-primed T cells without influencing their tumor necrosis factor-alpha production. These results suggest that GMP-140 binds to chronically stimulated CD4+ T cells and differentially modulates their production of proinflammatory cytokines. The ability of Ag-primed T cells to bind GMP-140 may facilitate interactions with activated platelets and endothelial cells affecting the course of inflammation.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
authors.forename: N K
authors.initials: NK
authors.lastname: Damle
authors.forename: K
authors.initials: K
authors.lastname: Klussman
authors.forename: M T
authors.initials: MT
authors.lastname: Dietsch
authors.forename: N
authors.initials: N
authors.lastname: Mohagheghpour
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D019041:L-Selectin; D008213:Lymphocyte Activation; D009439:Neuraminidase / Q000494:pharmacology; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D014357:Trypsin / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D019041:L-Selectin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009439:Neuraminidase; D014357:Trypsin