Structure and expression of CD40 and its ligand

The CD40 antigen, a 45-50 kDa glycoprotein of 277 amino acids, is a member of the tumor necrosis factor receptor family. The 193 amino acid extracellular domain is composed of four imperfect repeats of approximately 40 residues, anchored by a superimposable pattern of six cysteines. This organization is found in the other members of the superfamily including: the p75 low-affinity nerve growth factor receptor; the p55/CD120a and p75/CD120b receptors for tumor necrosis factor; the receptor (TNF-R rp) for the lymphotoxin a/lymphotoxin (J membrane complex; CD27 and CD30; 0X40; 4-1-BB/ILA; Fas/CD95; and two viral homologs of the TNF receptors. The X-ray crystal structure of the complex formed by soluble binding domains of p55 TNF-R and a lymphotoxin a trimer suggests that CD40 looks like a slightly bent rod. Three CD40 subunits are likely to engage the CD40-L trimer and scrupulously avoid contact between each other. The mouse CD40 gene, composed of nine exons that span 16.3 kb of genomic DNA, is located on the distal region of chromosome 2, which is syntenic to human chromosome 20qll-ql3, where the human CD40 gene is located. CD40 is expressed by multiple cell types. In the hematopoietic system, it is expressed on CD34' hematopoietic progenitors, B cell progenitors, mature B lymphocytes, plasma cells, monocytes, dendritic cells and on some T lymphocytes. CD40 is also expressed on nonhematopoietic cells such as endothelial cells, fibroblasts and epithelial cells. In 1992, expression cloning using a CD40-Fc fusion protein allowed the isolation of a CD40-L from activated T cells. The human CD40-L is a polypeptide of 261 amino acids, including a 215 amino acid extracellular domain with five cysteines. CD40-L is a member of the tumor necrosis factor (TNF) family that includes TNFa, LTa, LTp, CD27-L/CD70, CD30-L, 4-1BB-L, OX40-L, Fas-L and TRAIL. The gene for CD40-L is located on the X-chromosome position q26.3-q23.1. It spans over 12-13 kb and consists of five exons. CD40-L is readily expressed on CD4' and CD8+ T cells after activation through pathways that are inhibited by cyclosporine. Basophils, eosinophils and activated B lymphocytes have also been reported as expressing CD40-L.

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