Regulation of mouse 4-1BB expression: Multiple promoter usages and a splice variant
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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.
Keywords4-1BB NF-κB promoter splice variant
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- Goodwin, R.G., Din, W.S., Davis-Smith, T., Anderson, D.M., Gimpel, S.D., Sato, T.A., Maliszewski, C.R., Brannan, C.I., Copeland, N.G., Jenkins, N.A., et al. (1993). Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur. J. Immunol. 23, 2631–2641.PubMedCrossRefGoogle Scholar
- Heinisch, I.V., Bizer, C., Volgger, W., and Simon, H.U. (2001). Functional CD137 receptors are expressed by eosinophils from patients with IgE-mediated allergic responses but not by eosinophils from patients with non-IgE-mediated eosinophilic disorders. J. Allergy Clin. Immunol. 108, 21–28.PubMedCrossRefGoogle Scholar
- Kohno, T., Brewer, M.T., Baker, S.L., Schwartz, P.E., King, M.W., Hale, K.K., Squires, C.H., Thompson, R.C., and Vannice, J.L. (1990). A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc. Natl. Acad. Sci. USA 87, 8331–8335.PubMedCrossRefGoogle Scholar
- Michel, J., Langstein, J., Hofstadter, F., and Schwarz, H. (1998). A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur. J. Immunol. 28, 290–295.PubMedCrossRefGoogle Scholar
- Pizzolo, G., Vinante, F., Chilosi, M., Dallenbach, F., Josimovic-Alasevic, O., Diamantstein, T., and Stein, H. (1990). Serum levels of soluble CD30 molecule (Ki-1 antigen) in Hodgkin’s disease: relationship with disease activity and clinical stage. Br. J. Haematol. 75, 282–284.PubMedCrossRefGoogle Scholar
- Seko, Y., Sugishita, K., Sato, O., Takagi, A., Tada, Y., Matsuo, H., Yagita, H., Okumura, K., and Nagai, R. (2004). Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu’s arteritis. J. Vasc. Res. 41, 84–90.PubMedCrossRefGoogle Scholar
- Shuford, W.W., Klussman, K., Tritchler, D.D., Loo, D.T., Chalupny, J., Siadak, A.W., Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., et al. (1997). 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47–55.PubMedCrossRefGoogle Scholar