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, cynomolgus 4-1BB shares 95%, 57%, and 57% aa sequence identity with human, mouse, and rat 4-1BB, respectively. 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 co-stimulates 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 co‑stimulates 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).