The Bcl-xγ cytosolic protein is essential for costimulatory activity after CD3/CD28 coligation. Here we delineate the Bcl-xγ/Bcl-x genomic organization and the molecular mechanism that allows expression. We show that exon 4 of the Bcl-x gene encodes the unique C-terminal end of the Bcl-xγ molecule while exons 5, 6, 7 and 8 are differentially transcribed to yield three alternative Bcl-xγ 3′ untranslated regions (UTR). CD28-dependent signals may increase levels of Bcl-xγ protein through induction of an alternatively-spliced Bcl-xγ 3′ UTR that contains stem loop structures that stabilize Bcl-xγ RNA. The ability receptor-induced signals to regulate the splicing pattern of the complex Bcl-x gene may allow T-cells to respond appropriately to antigenic stimuli. © 2002 Elsevier Science Ltd. All rights reserved.