T-cell-specific surface glycoprotein CD28 (costimulatory domain) (CD28)

The CD28 costimulatory domain is a critical component of second-generation chimeric antigen receptor (CAR) T-cell therapies, providing the necessary secondary signal for robust T-cell activation and proliferation (PubMed: 28939538). Derived from the intracellular portion of the endogenous CD28 receptor (UniProt: P16284), this domain facilitates signal transduction through the PI3K/Akt and Grb2 pathways upon engagement of the CAR with its target antigen (PubMed: 30241463). In the context of CAR T cells, the inclusion of the CD28 domain is associated with rapid expansion, high peak effector function, and significant cytokine production, particularly interleukin-2 (PubMed: 25939063). These characteristics make it highly effective for inducing rapid tumor debulking in hematologic malignancies such as large B-cell lymphoma and mantle cell lymphoma (FDA: Yescarta Label). However, the intense signaling profile of CD28-based CARs is often linked to a higher risk of cytokine release syndrome (CRS) and neurotoxicity compared to other costimulatory domains like 4-1BB (PubMed: 31333907). Clinically, the CD28 domain is a defining feature of FDA-approved therapies such as axicabtagene ciloleucel and brexucabtagene autoleucel. Ongoing research focuses on modulating CD28 signaling to balance potent anti-tumor activity with improved safety and long-term T-cell persistence.

Other names

CD28 signaling domainCD28 endodomainCD28 intracellular domainTp44T-cell-specific surface glycoprotein CD28

Provides costimulatory signals via the PI3K/Akt and Grb2 pathways to enhance T cell effector function, proliferation, and survival upon CAR-antigen binding (PubMed: 30241463).