CD40CD40L

CD40CD40L refers to the receptor–ligand pair formed by CD40, a member of the TNF receptor superfamily, and its ligand CD40L (CD154). CD40 is widely expressed on antigen-presenting cells such as B cells, dendritic cells, macrophages, as well as endothelial and some epithelial cells. CD40L is primarily expressed on activated CD4+ T cells but can be found on platelets and other cells under certain conditions. The interaction between CD40 and CD40L provides a key costimulatory signal that modulates innate and adaptive immunity.

Signaling through CD40 involves the recruitment of TRAF adaptor proteins, activating NF-κB, MAPK, and other pathways. In B cells, this promotes activation, proliferation, isotype switching, germinal center formation, and differentiation into plasma cells. In dendritic cells and macrophages, CD40 engagement enhances maturation, cytokine production, and the ability to prime CD8+ T cells. The axis also supports T cell priming and inflammatory responses, reinforcing coordinated immune reactions.

Clinical relevance includes its essential role in humoral immunity, with deficiencies in CD40L causing X-linked Hyper-IgM syndrome due to impaired class-switch recombination. Therapeutically, the CD40–CD40L axis is explored for cancer and autoimmune diseases. Agonistic anti-CD40 antibodies aim to boost anti-tumor immunity by activating antigen-presenting cells, whereas approaches that block CD40–CD40L signaling seek to dampen excessive immune activation in autoimmunity or transplantation. Development of anti-CD40L antibodies has faced safety challenges, notably thromboembolic events, which has limited their clinical use. Ongoing research continues to refine approaches that balance efficacy and safety in modulating this pathway.