CD40 Ligand (CD40L), also known as TNFSF, CD154, TRAP, and gp39, is a 34-39 kDa type II transmembrane glycoprotein that belongs to the TNF superfamily [1-3]. Mature human CD40 Ligand consists of a 22 amino acid (aa) cytoplasmic domain, a transmembrane segment, and an 215 aa extracellular region [4, 5]. The extracellular domain of human CD40 Ligand shares 74% and 76% aa sequence identity with mouse and rat CD40 Ligand, respectively. Similar to other TNF superfamily members, CD40 Ligand forms a bioactive homotrimer, both as membrane bound and soluble forms [6-9]. The 18 kDa soluble form (aa 113-261) arises from proteolytic processing. Mutation and alternative splicing generate additional forms of CD40 Ligand that are often truncated or non-trimerizable [8]. CD40 Ligand is expressed on platelets, as well as on activated T cells and B cells, basophils, eosinophils, fibroblasts, mast cells, monocytes, natural killer cells, vascular endothelial cells, and smooth muscle cells. CD40 Ligand binds to CD40, which is expressed on the surface of B cells, dendritic cells, macrophages, monocytes, platelets, endothelial, and epithelial cells (10). The interaction of CD40 Ligand with CD40 initiates signaling in both CD40 and CD40 Ligand expressing cells [11]. CD40 ligation by CD40 Ligand promotes B cell activation and T cell-dependent humoral responses [12, 13]. CD40 Ligand dysregulation on T cells and antigen presenting cells contributes to the immune deficiency associated with HIV infection and AIDS [14, 15]. It is also implicated in the pathology of multiple cardiovascular diseases including atherosclerosis, atherothrombosis, and restenosis [16, 17].
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