CD40–CD40 ligand (CD154) costimulatory pathway (CD40–CD40L)

The CD40–CD40 ligand (CD40L, also known as CD154) interaction is a fundamental costimulatory signaling axis that mediates the activation of the adaptive immune response (UniProt P25942, P29965). CD40 is a transmembrane receptor of the tumor necrosis factor receptor (TNFR) superfamily expressed on antigen-presenting cells (APCs) like dendritic cells and B cells, while CD40L is primarily expressed on activated T cells (Elgueta et al., 2009). The binding of CD40L to CD40 "licenses" dendritic cells, enhancing their ability to process antigens and activate cytotoxic T cells and Cytokine-Induced Killer (CIK) cells (Vonderheide, 2020). In oncology, therapeutic agonists like Selicrelumab are used to stimulate this pathway to promote anti-tumor immunity, whereas in autoimmunity and transplantation, antagonists like Iscalimab are employed to suppress pathogenic immune activation (ClinicalTrials.gov). Clinical development of CD40 agonists has faced challenges such as cytokine release syndrome and hepatotoxicity, while early CD40L inhibitors were hindered by thromboembolic risks (Piechutta & Beckhove, 2019). Modern therapeutic strategies focus on optimizing the therapeutic window through bispecific antibodies or localized delivery.

Other names

CD40-CD154 interactionCD40-TNFSF5 interactionCD40-CD40L axisCD40-CD154 costimulatory pathwayCD40-CD40L costimulatory interaction

Agonism of CD40 to stimulate dendritic cell maturation and T-cell priming; Antagonism of CD40 or CD40L to inhibit costimulatory signaling and suppress immune responses (Vonderheide, 2020; Elgueta et al., 2009).