4-1BB, also known as CD137 and TNFRSF9, is an approximately 30 kDa transmembrane glycoprotein in the TNF receptor superfamily. 4-1BB functions in the development and activation of multiple immune cells (1). Mature human 4-1BB consists of a 163 amino acid (aa) extracellular domain (ECD) with four TNFR cysteine-rich repeats, a 27 aa transmembrane segment, and a 42 aa cytoplasmic domain (2, 3). Within the ECD, human 4-1BB shares 60% aa sequence identity with mouse and rat 4-1BB. 4-1BB is expressed as a disulfide-linked homodimer on various populations of activated T cell including CD4⁺, CD8⁺, memory CD8⁺, NKT, and regulatory T cells (4-7) as well as on myeloid and mast cell progenitors, dendritic cells, mast cells, and bacterially infected osteoblasts (8-11). It binds with high affinity to the transmembrane 4-1BB Ligand/TNFSF9 which is expressed on antigen presenting cells and myeloid progenitor cells (3, 8). This interaction costimulates the proliferation, activation, and/or survival of the 4-1BB expressing cell (3-7). It can also enhance the activation-induced cell death of repetitively stimulated T cells (3). Mice lacking 4-1BB show augmented T cell activation, perhaps due to its absence on regulatory T cells (12). 4-1BB can associate with OX40 on activated T cells, forming a complex that responds to either ligand and inhibits Treg and CD8⁺ T cell proliferation (13). Reverse signaling through 4-1BB Ligand inhibits the development of dendritic cells, B cells, and osteoclasts (8, 11) but supports mature dendritic cell survival and costimulates the proliferation and activation of mast cells (9, 10).
4-1BB activation enhances CD8⁺ T cell and NK cell mediated anti-tumor immunity (14). It also contributes to the development of inflammation in high fat diet-induced metabolic syndrome (15). Soluble forms of 4-1BB and 4-1BB Ligand circulate at elevated levels in the serum of rheumatoid arthritis and hematologic cancer patients, respectively (16, 17).

References

Wang, C. et al. (2009) Immunol. Rev. 229:192.
Schwarz, H. et al. (1993) Gene 134:295.
Alderson, M.R. et al. (1994) Eur. J. Immunol. 24:2219.
Wen, T. et al. (2002) J. Immunol. 168:4897.
Pulle, G. et al. (2006) J. Immunol. 176:2739.
Zheng, G. et al. (2004) J. Immunol. 173:2428.
Kim, D. et al. (2008) J. Immunol. 180:2062.
Lee, S. et al. (2008) Nat. Immunol. 9:917.
Choi, B.K. et al. (2009) J. Immunol. 182:4107.
Nishimoto, H. et al. (2005) Blood 106:4241.
Saito, K. et al. (2004) J. Biol. Chem. 279:13555.
Lee, S. et al. (2005) J. Immunol. 174:6803.
Ma, B.Y. et al. (2005) Blood 106:2002.
Choi, B.K. et al. (2010) J. Immunol. 185:1404.
Kim, C. et al. (2011) Diabetes 60:3159.
Michel, J. et al. (1998) Eur. J. Immunol. 28:290.
Salih, H.R. et al. (2001) J. Immunol. 167:4059.

Alternate Names

41BB, CD137, ILA, TNFRSF9

Entrez Gene IDs

3604 (Human); 21942 (Mouse); 500590 (Rat); 102127961 (Cynomolgus Monkey)

Gene Symbol

TNFRSF9

UniProt

Q07011

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This product is provided under an intellectual property license from Life Technologies Corporation. The transfer of this product is conditioned on the buyer using the purchased product solely in research conducted by the buyer, excluding contract research or any fee for service research, and the buyer must not (1) use this product or its components for (a) diagnostic, therapeutic or prophylactic purposes; (b) testing, analysis or screening services, or information in return for compensation on a per-test basis; or (c) manufacturing or quality assurance or quality control, and/or (2) sell or transfer this product or its components for resale, whether or not resold for use in research. For information on purchasing a license to this product for purposes other than as described above, contact Life Technologies Corporation, 5781 Van Allen Way, Carlsbad, CA 92008 USA or outlicensing@thermofisher.com.

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Human 4-1BB/TNFRSF9/CD137 Alexa Fluor™ Plus 555-conjugated Antibody

R&D Systems, part of Bio-Techne | Catalog # FAB8381AFP555

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Background: 4-1BB/TNFRSF9/CD137