Dual immunoregulatory pathways of 4-1BB signaling

It is perhaps rare to encounter among the various immunologically competent receptor–ligand pairs that a single cell surface determinant unleashes both a hidden suppressive function and costimulation. 4-1BB, an activation-induced tumor necrosis factor receptor family member chiefly viewed as a powerful T-cell costimulatory molecule, is one such example. Accumulated evidence in recent years uncovered an unknown facet of in vivo 4-1BB signaling (i.e., “active suppression”). Although in vitro signaling via 4-1BB is shown to support both CD4+ and CD8+ T-cell responses, the same induces a predominant CD8+ T-cell response suppressing CD4+ T-cell function when applied in vivo. How, when, and why such dual immunoregulatory effect of anti-4-1BB monoclonal antibody (MAB) comes into play is currently the focus of intense research. Existing data, although not complete, uncover several important aspects of in vivo 4-1BB signaling in the amelioration or exacerbation of various immune disorders. Despite minor disagreements, a majority agree that upregulation of interferon (IFN)-γ is critical to anti-4-1BB MAB therapy in addition to immune modulators such as interleukin 2, transforming growth factor β, and indolamine 2,3-dioxygenase5, all of which contribute greatly to the success of anti-4-1BB MAB-based immunotherapy. Anti-4-1BB MAB-mediated expansion of novel CD11c+CD8+ T cells is additional weaponry that appears critical for its in vivo suppressive function. These CD11c+CD8+ T cells express high levels of IFN-γ, become effective killers, and mediate selective suppression of CD4+ T cells. In this review, we discuss the dual nature (costimulatory and suppressive) of 4-1BB-mediated immune regulation, its current status, future direction, and its impact on the immune system, with special reference to its immunotherapy.