CD28–CD3ζ T-cell signaling complex (CD28-CD3ζ)

The CD28–CD3ζ T-cell signaling complex is a synthetic intracellular signaling architecture that serves as the functional core of second-generation Chimeric Antigen Receptors (CARs) (Sadelain et al., Nature, 2013). It is composed of the cytoplasmic signaling domain of the CD28 costimulatory receptor (UniProt P10747) fused to the CD3ζ (CD247) chain of the T-cell receptor (TCR) complex (UniProt P20963). This fusion allows engineered T cells to bypass the requirement for Major Histocompatibility Complex (MHC) presentation and professional costimulation, instead triggering full T-cell activation upon binding to a specific surface antigen (June et al., Science, 2018). Biologically, the CD3ζ component provides the primary activation signal through its immunoreceptor tyrosine-based activation motifs (ITAMs), while the CD28 component provides a costimulatory signal that enhances cytokine production, glucose metabolism, and rapid proliferation. In clinical practice, this complex is a critical component of FDA-approved therapies like Axicabtagene ciloleucel (Yescarta) used to treat various B-cell malignancies (FDA, Yescarta Prescribing Information). While highly effective at inducing rapid tumor clearance, the CD28–CD3ζ signaling profile is often associated with significant safety concerns, including cytokine release syndrome (CRS) and neurotoxicity, due to the intense and rapid nature of the T-cell activation it induces. This signaling domain is characterized by faster kinetics and higher peak cytokine levels compared to 4-1BB-based domains, which influences the metabolic state and persistence of the therapeutic T cells.

Other names

CD28-CD247 signaling domainSecond-generation CAR signaling domainCD28-CD3zeta fusion proteinCD28-CD3z28z

Provides dual-signal T-cell activation by combining primary TCR-like stimulation via CD3ζ ITAMs with costimulation via the CD28 cytoplasmic domain, bypassing MHC restriction.