Cluster of differentiation 28 (CD28) signaling complex (CD28)

The Cluster of differentiation 28 (CD28) signaling complex is a pivotal co-stimulatory system essential for the full activation of T-lymphocytes (UniProt P10747). CD28 is a homodimeric glycoprotein constitutively expressed on the surface of T-cells that binds to its ligands, CD80 (B7-1) and CD86 (B7-2), located on antigen-presenting cells (StatPearls: T Cell Activation). This interaction provides the necessary "Signal 2" that works in tandem with the T-cell receptor (TCR) "Signal 1" to promote cell cycle progression, cytokine production (notably IL-2), and cell survival (PubMed: PMC2691825). The signaling complex involves the recruitment of intracellular proteins such as PI3K, Grb2, and Vav1, which amplify downstream pathways like NF-κB and NFAT. In clinical practice, the CD28 pathway is a major target for treating autoimmune diseases and preventing organ transplant rejection by using inhibitors like Abatacept that block the B7-CD28 interaction (FDA: Orencia Label). Conversely, agonistic targeting of CD28 has been explored for cancer immunotherapy to enhance the body's anti-tumor response. However, therapeutic manipulation of this complex requires careful management, as potent agonism can lead to life-threatening cytokine release syndrome, as seen in the TGN1412 clinical trials (PubMed: 16929030). Chronic blockade of this signaling complex may also increase the risk of opportunistic infections and certain malignancies due to prolonged immunosuppression.

Other names

CD28T-cell-specific surface glycoprotein CD28Tp44CD28 molecule

Modulation of T-cell co-stimulation by either blocking the CD28-CD80/86 interaction (via CTLA4-Ig or anti-CD28 antibodies) to induce immunosuppression or agonistically stimulating CD28 to enhance immune responses (PubMed: PMC2691825).