Biological activities of reverse signal transduction through CD137 ligand

CD137 is a member of the tumor necrosis factor receptor family and a potent regulator of T cell activities. Agonists of CD137 have been used widely and successfully to treat cancer in animal models, and recently, it has become evident that CD137 agonists can also be used to treat autoimmune disease. An aspect of the CD137 receptor/ligand system, which has been comparatively little‐explored, is its ability of reverse signaling. Just as is CD137, the CD137 ligand is also expressed as a cell membrane protein, and it too can transduce signals into the cells on which it is expressed. This bidirectional signaling capacity allows the CD137 receptor/ligand system to mediate extensive cross‐talk between immune cells and between immune and nonimmune cells. This review summarizes the known activities of the CD137 ligand on the different leukocyte subsets and on cancer cells and discusses their influence on the course of immune responses.