Tumor necrosis factor receptor superfamily member 9 (4-1BB) intracellular signaling domain (4-1BB)

The intracellular signaling domain of Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), commonly known as 4-1BB or CD137, is a critical component used in the design of second-generation chimeric antigen receptors (CARs) for T-cell therapy. In its native biological role, 4-1BB acts as a potent costimulatory molecule on activated T cells, providing signals that promote survival, proliferation, and the development of immunological memory (UniProt Consortium, 2023). When integrated into an engineered CAR construct, this cytoplasmic domain provides essential costimulatory signals upon antigen binding, typically working in tandem with the CD3-zeta signaling chain (Long et al., 2015). Compared to other costimulatory domains like CD28, the 4-1BB domain is associated with slower T-cell expansion but significantly enhanced long-term persistence and a metabolic profile favoring oxidative phosphorylation (Kawalekar et al., 2016). This persistence is vital for sustained anti-tumor activity, particularly in the treatment of hematologic malignancies such as B-cell lymphomas and multiple myeloma. Several FDA-approved CAR-T cell therapies, including Tisagenlecleucel and Lisocabtagene maraleucel, utilize the 4-1BB signaling domain to achieve durable clinical responses (FDA, 2017; FDA, 2021). The domain functions by recruiting Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), which subsequently activate the NF-kappaB and MAPK signaling pathways to prevent activation-induced cell death (Watts, 2005; Salter et al., 2018).

Other names

CD137TNFRSF9Induced by lymphocyte activation (ILA)4-1BB costimulatory domainCD137 cytoplasmic tail

Recruitment of TRAF1, TRAF2, and TRAF3 adapter proteins to the cytoplasmic tail, triggering NF-kappaB, c-Jun N-terminal kinase (JNK), and p38 MAPK signaling pathways to enhance T-cell persistence and oxidative metabolism.