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

The 4-1BB (CD137) intracellular costimulatory domain is a critical component of second and third-generation Chimeric Antigen Receptor (CAR) T-cell therapies (PMID: 28939538). Derived from the Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), this domain provides essential secondary signals that augment T-cell activation following antigen recognition by the CAR's extracellular binding domain (UniProt: P41273). Unlike the CD28 costimulatory domain, which triggers rapid effector responses and glycolysis, the 4-1BB domain promotes mitochondrial biogenesis and oxidative phosphorylation, leading to enhanced T-cell persistence and the formation of memory-like T-cell phenotypes (PMID: 31110339). This metabolic reprogramming allows CAR-T cells to survive longer in the patient's body, which is often correlated with sustained clinical remissions in hematologic malignancies (PMID: 21830940). Signaling through the 4-1BB domain is mediated by the recruitment of Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), particularly TRAF1 and TRAF2, which activate the NF-κB and MAPK pathways (PMID: 29739443). Clinically, 4-1BB-based CAR-T cells, such as Tisagenlecleucel and Lisocabtagene maraleucel, are associated with a distinct safety profile, typically exhibiting slower expansion kinetics and potentially lower rates of severe cytokine release syndrome compared to CD28-based constructs (FDA: Kymriah Prescribing Information).

Other names

CD137TNFRSF9Induced by Lymphocyte Activation (ILA)4-1BB costimulatory domain

Provides costimulatory signaling via the recruitment of Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), specifically TRAF1 and TRAF2, to activate NF-κB, MAPK, and PI3K/Akt pathways, which enhances CAR-T cell persistence and metabolic fitness (PMID: 31110339, PMID: 29739443).