Cluster of Differentiation 28 costimulatory domain (CD28) (CD28)

The CD28 costimulatory domain is a synthetic intracellular signaling component used in second-generation Chimeric Antigen Receptors (CARs) to mimic the natural costimulatory signal of T cells (PubMed: 25939063). Derived from the CD28 receptor, a member of the immunoglobulin superfamily, this domain is typically fused to the CD3-zeta chain to provide "Signal 2," which is essential for full T-cell activation and preventing anergy (PubMed: 28111400). In CAR-T cell therapy, the CD28 domain facilitates rapid T-cell expansion and potent effector functions by activating the PI3K/Akt and PLC-gamma-1 signaling pathways (PubMed: 30204206). Compared to other costimulatory domains like 4-1BB, CD28-based CARs generally exhibit faster kinetics of activation and a shift toward glycolytic metabolism, though they may show reduced long-term persistence (PubMed: 26877974). This domain is a core feature of several FDA-approved therapies, including Axicabtagene ciloleucel, used to treat aggressive B-cell lymphomas (FDA: Yescarta Label). While highly effective, the intense signaling of the CD28 domain is associated with a higher incidence of rapid-onset cytokine release syndrome (CRS) and neurotoxicity (PubMed: 31333912).

Other names

CD28 intracellular domainCD28 endodomainCD28 signaling domainCD28 cytoplasmic tail

Provides costimulatory signaling (Signal 2) via the PI3K/Akt pathway to enhance T-cell effector function and proliferation following antigen recognition by the CAR (PubMed: 30204206).