Second-generation Chimeric Antigen Receptor signaling domain (4-1BB and CD3ζ) (BBζ)

The engineered T-cell signaling machinery via CD3ζ and 4-1BB represents the intracellular signaling component of second-generation Chimeric Antigen Receptors (CARs). This synthetic construct combines the primary activation signal from the CD3ζ (CD247) chain with the costimulatory signal from 4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily [PubMed: 21807999]. Upon binding of the CAR's extracellular domain to a specific tumor antigen, the CD3ζ domain triggers T-cell activation through its immunoreceptor tyrosine-based activation motifs (ITAMs), while the 4-1BB domain enhances T-cell expansion, metabolic fitness, and long-term persistence [PubMed: 26928466]. This specific signaling configuration is utilized in several FDA-approved CAR-T cell therapies, including Tisagenlecleucel and Lisocabtagene maraleucel, which have revolutionized the treatment of refractory B-cell malignancies [FDA.gov]. By providing both Signal 1 and Signal 2 in a single molecule, this machinery allows T cells to bypass traditional MHC-restricted activation and mount a potent, sustained anti-tumor response. However, the intense immune activation can lead to severe side effects such as cytokine release syndrome (CRS) and neurotoxicity, requiring careful clinical management [PubMed: 29245008].

Other names

4-1BB/CD3ζ signaling endodomainCD137/CD3zeta CAR signaling machinerySecond-generation CAR endodomainBBζ signaling domain

The signaling machinery functions by transducing extracellular antigen-binding events into intracellular activation signals. The CD3ζ domain initiates T-cell receptor-like signaling via ITAM phosphorylation, while the 4-1BB domain provides costimulation through the recruitment of TRAF adapter proteins, activating NF-κB and PI3K/Akt pathways to enhance survival and persistence [PubMed: 21807999, 26928466].