The CD40/CD154 receptor/ligand dyad

Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines, matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory processes and prevalent human diseases.