Genes, Transcripts and Proteins of CD137 Receptor and Ligand
CD137 and CD137L belong to the tumor necrosis factor (TNF) superfamily, a group of cysteine-rich cell surface molecules.With a few exceptions, both CD137 and its ligand, CD137L, are activation induced. CD137 activates CD8+ T cells more strongly than CD4+ T cells, and is a potent inducer of IFN-γ. Stimulation through CD137L also relays activation signals toBcells and monocytes. These signals elicit activation of NF-κB via the TRAF-NIK pathway and lead to the induction of a plethora of immune modulators that accentuate the ongoing immune reaction. CD137 and CD137L-deficient mice develop normally, have normal numbers of T and B cells and only demonstrate modest immune malfunction. However, in vivo administration of agonistic anti-CD137 mAb protects strongly against a variety of autoimmune and non-autoimmune diseases. The basis of this protection is unclear; however, it seems to involve an indoleamine dioxygenase (IDO)-dependent process in which pathogenic T cells are killed/suppressed by “regulatory CD11c+CD8+ T cells.” In this review, the origins and functional features of CD137 and CD137L are discussed.
KeywordsTumor Necrosis Factor Receptor CD137 Receptor Soluble CD137 Acute Myocarditis CD137 Transcript
Unable to display preview. Download preview PDF.
- DeBenedette, M.A., Wen, T., Bachmann, M.F., Ohashi, P.M., Barber, B.H., Stocking, K.L., Peschon, J.J., and Watts, T.H. (1999). Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus. J. Immunol., 163, 4833–4841.PubMedGoogle Scholar
- Diehl, L., van Mierlo, G.J., den Boer, A.T., van der Voort, E., Fransen, M., van Bostelen, L., Krimpenfort, P., Melief, C.J., Mittler, R., Toes, R.E., and Offringa, R. (2002). In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway. J. Immunol., 168, 3755–3762.PubMedGoogle Scholar
- Foell, J., Strahotin, S., O’Neil, S.P., McClausland, M.M., Suwyn, C., Haber, M., Chander, P.N., Bapat, A.S., Yan, X.J., Chiorazzi, N., Hoffmann, M.K., and Mittler, R.S. (2003). CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB × NZW F1 mice. J. Clin. Invest., 111, 1505–1518.PubMedCrossRefGoogle Scholar
- 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., Farrah, T., Armitage, R.J., Fanslow, W.C., and Smith, C.A. (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
- Salih, H.R., Schmetzer, H.M., Burke, C., Straling, G.C., Dunn, R., Pelka-Fleiscischer, R., Nuessler, V., and Kiener, P.A. (2001). Soluble CD137 (4-1BB) ligand is released following leukocyte activation and is found in sera of patients with hematological malignancies. J. Immunol., 167, 4059–4066.PubMedGoogle Scholar
- Seko, Y., Takahashi, N., Oshima, H., Shimozato, O., Akiba, H., Takeda, K., Kobata, T., Yagita, H., Okumura, K., Azuma, M., and Nagai, R. (2001). Expression of tumor necrosis factor (TNF) ligand superfamily costimulatory molecules CD30L, CD27L, OX40L, and 4-1BBL in murine hearts with acute myocarditis caused by coxsackievirus B3. J. Pathol., 195, 593–603.PubMedCrossRefGoogle Scholar
- Seko, H., Ishiyama, S., Nishikawa, T., Kasajima, T., Hiroe, M., Suzuki, S., Ishiwata, S., Kawai, S., Tanaka, Y., Azuma, M., Kobata, T., Yagita, H., Okumura, K., and Nagai, R. (2002). Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L, CD30L, OX40L, and 4-1BBL in the heart of patients with acute myocarditis and dilated cardiomyopathy. Cardiovasc. Pathol., 11, 166–170.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., Pearson, T.C., Ledbetter, J.A., Aruffo, A., and Mittler, R.S. (1997). 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell response. J Exp Med., 186, 47–55.PubMedCrossRefGoogle Scholar
- Wan, Y.L., Zheng, S.S., Zhao, Z.C., Li, M.W., Jia, C.K., and Zhang, H. (2004). Expression of co-stimulator 4-1BB molecule in hepatocellular carcinoma and adjacent non-tumor liver tissue, and its possible role in tumor immunity. World J. Gastroenterol., 10, 195–199.Google Scholar
- Yndestad, A., Damas, J.K., Geir Eiken, H., Holm, T., Hauh, T., Simonsen, S., Froland, S.S., Gullestad, L., and Aukrust, P. (2002). Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure. Cardiovasc. Res., 54, 175–182.PubMedCrossRefGoogle Scholar