Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) intracellular signaling domain (4-1BB ICD)

The 4-1BB intracellular signaling domain is a critical cytoplasmic component of the Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), also known as CD137 (UniProt: Q07011). In natural T-cell biology, this domain mediates costimulatory signals upon binding to its ligand (4-1BBL), primarily through the recruitment of Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), which activate the NF-kappaB and MAPK signaling pathways (PubMed: 15123770). This activation enhances T-cell proliferation, survival, and effector function while preventing activation-induced cell death. In the context of modern immunotherapy, the 4-1BB intracellular domain is widely utilized as a costimulatory element in second-generation Chimeric Antigen Receptor (CAR) T-cell therapies, such as Tisagenlecleucel and Lisocabtagene maraleucel (FDA). Compared to other costimulatory domains like CD28, the 4-1BB domain is associated with increased mitochondrial biogenesis, slower T-cell exhaustion, and superior long-term persistence of CAR-T cells in vivo (PubMed: 26030179). Consequently, it plays a pivotal role in the clinical success of several approved CAR-T products for treating various hematologic malignancies.

Other names

CD137 intracellular domain4-1BB cytoplasmic domainTNFRSF9 cytoplasmic tailCD137 ICD4-1BB signaling tail

Recruitment of TRAF1, TRAF2, and TRAF3 adapter proteins to initiate downstream signaling cascades including NF-kappaB, JNK, and p38 MAPK, which collectively promote T-cell metabolic fitness, longevity, and sustained effector function (PubMed: 26030179).