T-cell-specific surface glycoprotein CD28 (co-stimulatory domain) (CD28)

The CD28 co-stimulatory domain is a pivotal intracellular signaling component incorporated into second-generation Chimeric Antigen Receptors (CARs) to provide the essential secondary signal for full T-cell activation (UniProt P10747). In its native physiological context, CD28 is a homodimeric glycoprotein expressed on T-cells that interacts with CD80/CD86 ligands on antigen-presenting cells to promote cell cycle progression, IL-2 production, and survival (Esensten et al., 2016, Immunity). When engineered into a CAR, the CD28 domain—typically the intracellular portion—facilitates rapid and robust T-cell expansion and potent effector function upon recognition of the target antigen (van der Stegen et al., 2015, Nature Reviews Drug Discovery). CD28-containing CAR-T cells, such as axicabtagene ciloleucel, are characterized by faster peak expansion and a predominantly glycolytic metabolism compared to those utilizing 4-1BB domains (Kawalekar et al., 2016, Immunity). However, this intense signaling can lead to faster T-cell exhaustion and is frequently associated with higher incidences of cytokine release syndrome (CRS) and neurotoxicity (FDA Prescribing Information for Yescarta). This domain remains a cornerstone of synthetic immunology, enabling the successful treatment of various B-cell malignancies.

Other names

CD28 intracellular domainCD28 signaling domainTp44T-cell-specific surface glycoprotein CD28CD28 molecule

Provides a co-stimulatory signal (Signal 2) via the PI3K/AKT and Grb2 pathways upon antigen binding to the CAR, enhancing T-cell effector functions, metabolic activity, and proliferation.