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.

Rhinovirus Infection Induces Expression of Its Own Receptor Intercellular Adhesion Molecule 1 (ICAM-1) via Increased NF-κB-mediated Transcription

“…Epithelial expression of ICAM-1 is likely to play an important function in retaining both types of inflammatory leukocyte in the epithelium by binding to its ligands CD18/11a and CD18/11b on lymphocytes and granulocytes, respectively. In addition, binding of ICAM-1 to its integrin ligands on leukocytes may activate these cells and lead to secretion of proinflammatory cytokines and mediators (43)(44)(45)(46). Induction of ICAM-1 expression on respiratory epithelial cells is therefore likely to be an important mechanism regulating the bronchial mucosal CD3 ϩ , CD4 ϩ , and CD8 ϩ lymphocyte and eosinophil infiltration observed in rhinovirus infections.…”

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…These include inflammatory gene activation. For example, Pselectin bound to antigen-primed CD4 þ T cells differentially modulates the production of pro-inflammatory cytokines (Damle et al, 1992), and thus T-cell activation may be facilitated via adhesion with activated platelets. Furthermore, CD11b/CD18 can modulate NF-kB activity via IL-1 receptor signalling pathway (Shi et al, 2001).…”

Intercellular adhesion molecule-1 inhibits interleukin 4 production by naive T cells

“…Compared with splenic APC, however, the class II plus B7 APC were relatively less efficient in that peak responses generally required higher concentrations of Ova peptide. Augmentation of T cell proliferative responses by interactions involving lymphocyte function-associated antigen-1 (LFA-1) and ICAM-1 is well documented (15,(24)(25)(26)(27). In keeping with these findings, coexpression of ICAM-1 and B7 (either B7.1 or B7.2) led to strong proliferative responses with very low concentrations of Ova peptide ( Fig.…”