Regulation of mouse 4-1BB expression: multiple promoter usages and a splice variant.

The expression of 4-1BB has been known to be dependent on T cell activation. Recent studies have, however, revealed that 4-1BB expression is not restricted to T cells. We sought to determine the molecular basis for the differential gene expression. Here we report the expression pattern of two mouse 4-1BB transcripts, type I and type II. Whereas the type I transcript was specifically expressed on immune organ as previously reported, the type II transcript was ubiquitously expressed in tissues and various cell lines. However, both type I and type II transcript were highly induced on activated T cells. Primer extension assay of the two 4-1BB transcripts suggested that mouse 4-1BB had more than two transcripts. Using luciferase assay we have identified three promoter regions (PI, PII and PIII), which located on upstream region of second exon 1, first exon 1, and exon 2, respectively. In particular, the type I transcript was preferentially induced when naïve T cells are stimulated by anti-CD3 monoclonal antibody (mAb) since NF-κB specifically binds to the putative NF-κB element of PI. We have also shown that a splice variant, in which the transmembrane domain was deleted, could inhibit 4-1BB signaling. The splicing variant was highly induced by TCR stimulation. Our results reveal 4-1BB also has a negative regulation system through soluble 4-1BB produced from a splice variant induced under activation conditions.