CD137 ligand (CD137L) is a costimulatory ligand that is expressed on antigen-presenting cells (APCs) and is important for enhancing T cell activation by crosslinking CD137 on activated T cells. 1-3 While CD137 triggers a costimulatory signal in T cells, CD137L has been reported to trigger reverse signaling in APCs. 4 In human monocytes, reverse CD137L signaling leads to the differentiation of dendritic cells (DCs), which are termed CD137L-DCs. 5 CD137L-DCs are a novel type of DC and a potent candidate for DC-based cancer immunotherapy. CD137L-DCs are effective at polarizing Th1 and Tc1 responses and induce stronger cytotoxic T cell responses than those of monocytederived DCs generated with the more commonly used granulocyte-macrophage colony-stimulating factor and interleukin-4 (IL-4). 5-7

The differentiation of monocytes into CD137L-DCs by reverse CD137L signaling was thought to be mediated solely by CD137L, since neither the isolated Fc domain of human immunoglobulin G (IgG) nor isotype controls for anti-CD137L antibodies induced CD137L-DC differentiation. 5 The absence of CD137L-DCs in mice is consistent with the fact that human CD137L and mouse CD137L share little homology. 8 However, all studies relied on the use of immobilized CD137-Fc protein or anti-CD137L antibodies to crosslink CD137L. MCF-7 cells that were transfected to express CD137 failed to activate monocytic THP-1 cells to secrete IL-8 (Fig. 1 a), indicating that CD137L alone is not enough to trigger reverse CD137L signaling.