Regulation of CD40 function by its isoforms generated through alternative splicing

CD40 is a member of the tumor necrosis factor receptor superfamily. The int eraction between CD40 and CD40 ligand (CD154) activates NF-kappaB, Jun N-te rminal kinase, and Janus kinase/signal transducers and activators of transc ription pathways and promotes B cell growth, differentiation, and survival as well as IL-12 production in macrophages and dendritic cells. We demonstr ate here the existence of multiple isoforms of CD40 mRNA generated by alter native splicing and show that their expression is regulated differentially in activated macrophages and dendritic cells. Pre-CD40 RNA is spliced prefe rentially out to signal-transducible CD40 mRNA in the early stage of activa tion; half of the CD40 mRNA is replaced by the signal-nontransducible CD40 mRNAs in the later stages (24 h), Using IL-12 p40 gene expression as a repo rter for CD40 signaling, we show that three of the alternative isoforms can disable signaling through CD40, The major alternative isoform lacks the me mbrane-associated endodomain and seems to reduce the amount of the signal-t ransducible form available on the cell surface. It would seem, therefore, t hat CD40 expression is controlled by posttranscriptional and posttranslatio nal regulation through alternative splicing. Modulation of isoform expressi on may provide a mechanism by which cells regulate their susceptibility to CD40L signaling.