CD40-CD154 interaction in experimental and human disease (Review)

Cell-to-cell signals between T lymphocytes and antigen-presenting cells str ictly regulate the development of the immune response. It has clearly emerg ed that among these signals few cell surface receptor-ligand pairs, such as CD40 and its ligand, CD154, are mandatory for the induction of lymphocyte activation. The early observation that mutations of CD154 gene are responsi ble for a human severe immunodeficiency primed an impressive number of stud ies aimed to functionally characterize this receptorial system in view of t herapeutically exploiting its properties. Indeed, various approaches aimed to disrupt natural CD40-CD154 interaction were highly effective in the prev ention and treatment of several experimental models of autoimmune disease a nd transplant rejection. In parallel, abnormalities of this pathway were co nstantly found in several immunologically-mediated human diseases. Furtherm ore, a number of studies have dissected the role of CD40 and its ligand in the immune response against various microbial and viral pathogens. Since th ese molecules are often expressed by tumor cells, it is not surprising that great efforts have been made to address their function also in the develop ment of cancer. Most recent data strongly suggest an involvement of endothe lial CD40 in the vascular processes that lead to atherogenesis. This review focuses on the most significant advances in the understanding of the molec ular regulatory events involving CD40 and its ligand in experimental and hu man disease.