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

The Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), commonly known as 4-1BB or CD137, is a surface glycoprotein that functions as a potent costimulatory member of the TNF receptor family (UniProt: Q07011). In the design of second and third-generation Chimeric Antigen Receptors (CARs), the intracellular costimulatory domain (ICD) of 4-1BB is utilized to provide the necessary secondary signal for robust T-cell activation and longevity (PubMed: 28933255). Unlike CD28-based CARs, which often lead to rapid effector differentiation and exhaustion, the 4-1BB ICD promotes mitochondrial biogenesis and oxidative metabolism, favoring the development of central memory T-cells and long-term persistence in vivo (PubMed: 27226537). \n\nThis domain operates by recruiting Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), specifically TRAF1 and TRAF2, which trigger downstream NF-kappaB and MAPK/ERK signaling pathways (PubMed: 30206110). Clinically, the 4-1BB ICD is a core component of several approved therapies, such as Tisagenlecleucel and Lisocabtagene maraleucel, where it is critical for achieving sustained remission in B-cell malignancies (FDA Label: Kymriah, Breyanzi). While it generally exhibits a safer toxicity profile with slower expansion kinetics than CD28, it is still associated with significant risks like cytokine release syndrome (CRS) and neurotoxicity (PubMed: 29937173).

Other names

4-1BBCD137TNFRSF9Induced by lymphocyte activationILACDw137T-cell antigen 4-1BB homolog

The 4-1BB intracellular costimulatory domain functions by recruiting Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), primarily TRAF1 and TRAF2, which assemble signaling complexes that activate the NF-kappaB, c-Jun N-terminal kinase (JNK), and p38 MAPK pathways. In the context of a Chimeric Antigen Receptor (CAR), this signaling provides "Signal 2", which complements the "Signal 1" from the CD3-zeta domain to promote T-cell survival, metabolic reprogramming toward oxidative phosphorylation, and the formation of long-lived memory T-cells (PubMed: 28933255, PubMed: 27226537).