4-1BB Ligand Extracellular Domain (human, recombinant)

TNF ligand superfamily member 9 (4-1BB ligand) is a type II transmembrane glycoprotein and a member of the TNF superfamily.^1,2 It is composed of an N-terminal cytoplasmic region, a transmembrane domain, and a C-terminal extracellular tail region that contains a TNF homology domain.^2,3 4-1BB ligand production is induced in antigen-presenting cells (APCs), such as dendritic cells, B cells, and macrophages, by CD40 and toll-like receptor (TLR) activation.² It forms homotrimers and binds to its receptor, 4-1BB, on antigen-primed T cells, which induces NF-κB and MAPK signaling through TNF receptor-associated factors (TRAFs) and, when the T cell is co-stimulated by other factors, induces PI3K-Akt signaling.^1,2 This action promotes the proliferation of T cells, production of cytokines, and cell survival.² Soluble forms of 4-1BB ligand, consisting of only the extracellular domain, also form trimers that bind to its receptor but do not induce signaling.⁴ Mice deficient for 4-1BB ligand, Tnfsf9, have impairments in the formation of CD8⁺ T cell memory cells and in clearing pathogens.^2,5 Tnfsf9 knockout mice also develop B cell lymphomas before 12 months of age.⁶ 4-1BB ligand antibodies induce T regulatory cell expansion and prevent allogeneic graft rejection of pancreatic islets in mice.⁷ Intratumoral adenovirus-mediated gene transfer of Tnfsf9 induces tumor regression in a mouse syngeneic model of breast cancer.⁶ The protein levels of 4-1BB ligand are elevated in more than 40% of patients with acute myeloid leukemia (AML) or non-Hodgkin’s lymphoma but the expression of TNFSF9 is either elevated or reduced in cancer patients depending on the type of cancer. Cayman’s 4-1BB Ligand Extracellular Domain (human, recombinant) protein can be used for ELISA and binding assay applications. This protein is a disulfide-linked homodimer. The reduced monomer, comprised of 4-1BB ligand (amino acids 71-254) fused to human IgG1 Fc at the N-terminus, consists of 444 amino acids and has a calculated molecular weight of 47.9 kDa.

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1. Barsoumian, H.B., Batra, L., Shrestha, P., et al. A novel form of 4-1BBL prevents cancer development via nonspecific activation of CD4⁺ T and natural killer cells. Cancer Res. 79(4), 783-794 (2019).

2. So, T., and Ishii, N. The TNF–TNFR family of co-signal molecules. Co-signal molecules in T cell activation 53-84 (2019).

3. Bitra, A., Doukov, T., Croft, M., et al. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. The Journal of Biological Chemisty 293(26), 9958-9969 (2018).

4. Wyzgol, A., Müller, N., Fick, A., et al. Trimer stabilization, oligomerization, and antibody-mediated cell surface immobilization improve the activity of soluble trimers of CD27L, CD40L, 41BBL, and glucocorticoid-induced TNF receptor ligand. J. Immunol. 183(3), 1851-1861 (2009).

5. Wang, C., Lin, G.H.Y., McPherson, A.J., et al. Immune regulation by 4-1BB and 4-1BBL: Complexities and challenges. Immunol. Rev. 229(1), 192-215 (2009).

6. Vinay, D.S., and Kwon, B.S. Immunotherapy of cancer with 4-1BB. Mol. Cancer Ther. 11(5), 1062-1070 (2012).

7. Elpek, K.G., Yolcu, E.S., Franke, D.D.H., et al. Ex vivo expansion of CD4⁺CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling. J. Immunol. 179(11), 7295-7304 (2007).