title: Dual immunoregulatory pathways of 4-1BB signaling.
abstract: 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)-gamma is critical to anti-4-1BB MAB therapy in addition to immune modulators such as interleukin 2, transforming growth factor beta, and indolamine 2,3-dioxygenase(5), 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-gamma, 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.
authors.affiliation: LSU Eye Center, Louisiana State University Health Sciences Center School of Medicine, Suite B, 2020 Gravier Street, New Orleans, LA 70112, USA.
authors.forename: Dass S
authors.initials: DS
authors.lastname: Vinay
authors.forename: Kiweon
authors.initials: K
authors.lastname: Cha
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D006801:Humans; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal