TRANCE–RANK, a New Signal Pathway Involved in Lymphocyte Development and T Cell Activation

A lmost a decade ago, major advancements in our understanding of the cell–cell interactions that were critically involved in the regulation of the immune response were achieved when it was established that T cell activation not only required a signal through the T cell receptor but also a second signal generated by the interaction of costim-ulatory molecules CD80 and CD86 on the surface of APCs and CD28 or CTLA-4 on T cells (1). Since then, identification of other molecular interactions that are important in regulating the immune response has increased dramatically, elucidating signals that enhance stable cellular interactions between APCs and T cells as well as apoptotic signals that regulate survival of either the APC or the T cell (2, 3). One molecular interaction that has received enormous attention is that between CD40 on APCs and CD154 on T cells (reviewed in 4). CD40–CD154 signals are a vital component in the generation of humoral immunity, as exemplified by murine models in which blockade of CD40–CD154 signals , either by antibodies or the creation of a null mutation in CD154, abrogates development of B cell responses to thymus-dependent antigens (5, 6). Signals through CD40 can also influence the activity of other APCs, in particular dendritic cells (DCs), leading to the upregulation of adhesion and costimulatory molecules (7, 8), increased accumulation of peptide–MHC complexes on DC surfaces, and the generation of antiapoptotic signals that increase DC survival (9, 10), thus helping to prolong contact between DCs and T cells. Although the importance of CD40–CD154 interactions in the generation of B and T cell immunity are indisputable, findings that CD40-and CD154-deficient mice can mount T cell responses to certain viral infections have suggested a novel CD40–CD154-independent pathway involved in the activation of T cells (11–13). In this issue, Bachmann et al. (14) provide compelling evidence that this CD40–CD154-independent pathway for T cell activation involves interaction between a newly described molecule, TRANCE (TNF-related activation-induced cytokine), on T cells and its cognate receptor, RANK (receptor activator of NF ␬ B), on DCs. TRANCE (also called receptor activator of NF ␬ B ligand [RANKL], osteoprotegerin ligand [TRANCE/OPGL], and osteoclast differentiation factor [ODF]) was discovered almost simultaneously by two groups during attempts to clone novel genes involved in the regulation of apoptosis and function of DCs (15, 16). TRANCE is a member of the TNF ligand superfamily that includes Fas ligand, CD27, CD30, CD154, 4-1BBL, OX40L, TNF-␣ …