CD154

CD154, also known as CD40 ligand (CD40L), is a type II transmembrane glycoprotein of the tumor necrosis factor (TNF) superfamily. It is encoded by the CD40LG gene on the X chromosome. CD154 is primarily expressed on activated CD4+ T helper cells, but can also be found on platelets and other hematopoietic cells after activation. The protein forms a membrane-bound homotrimer and can be released as a soluble fragment by proteolytic cleavage.

CD154 binds to CD40, a receptor on B cells, dendritic cells, macrophages, and other antigen-presenting cells. This interaction provides essential “help” for T cell dependent B cell responses, promoting B cell activation, germinal center formation, isotype switching, and plasma cell differentiation. It also enhances dendritic cell maturation, cytokine production, and macrophage activation, thereby shaping adaptive and innate immune responses.

Clinical significance: Genetic deficiency of CD40L causes X-linked hyper-IgM syndrome, characterized by impaired class switch recombination, very high IgM and low IgG, IgA, and IgE, with recurrent infections and absent germinal centers. Overexpression or dysregulation of CD40L has been linked to autoimmune diseases and contributes to inflammation in various contexts. Therapeutically, CD40L or CD40-targeted strategies have been explored in transplantation and cancer, though anti-CD40L antibodies were associated with thrombotic complications, limiting their use.

In research and therapy, CD40–CD40L interactions remain a focus for modulating immune responses, including vaccine design and immunotherapy, with efforts to develop agents that activate or inhibit the pathway while minimizing adverse events.