T-cell-specific surface glycoprotein CD28 intracellular signaling domain (CD28 ICD)

The CD28 intracellular signaling domain (ICD) is the cytoplasmic portion of the CD28 cluster of differentiation, a pivotal co-stimulatory molecule expressed on the surface of T-cells (UniProt P10747). Upon engagement of the CD28 extracellular domain with its ligands, CD80 or CD86, the ICD facilitates the transmission of essential secondary signals that complement T-cell receptor (TCR) activation (Esensten et al., 2016, PMID: 26796619). It contains key signaling motifs, including a YMNM motif that recruits phosphoinositide 3-kinase (PI3K) and proline-rich regions that bind Grb2 and Lck, leading to the activation of the AKT and NF-kappaB pathways (PubMed: 23847187). These pathways drive T-cell proliferation, survival, and the robust production of cytokines such as interleukin-2 (IL-2). In the context of cancer immunotherapy, the CD28 ICD is a fundamental component of second-generation chimeric antigen receptors (CARs), providing the necessary co-stimulation to enhance the potency and expansion of engineered T-cells (FDA: Yescarta). While CD28-based CAR-T cells offer rapid and powerful anti-tumor responses, they are often associated with higher risks of cytokine release syndrome (CRS) and faster metabolic exhaustion compared to 4-1BB-based constructs (PubMed: 29937368). Therapeutic modulation of this domain's signaling is a key strategy in treating both malignancies and autoimmune disorders.

Other names

CD28 cytoplasmic domainCD28 endodomainCD28 signaling tailCD28 cytoplasmic tailCD28 cytosolic domain

The CD28 intracellular signaling domain functions by recruiting cytoplasmic signaling proteins to its phosphorylated tyrosine and proline-rich motifs, thereby amplifying T-cell receptor signals and activating the PI3K/AKT and Ras/MAPK pathways.