Robert S Mittler Liguo Niu Becker Hewes and Juergen Foell

CD137 (4-1BB), a member of the tumor necrosis factor receptor (TNFR) superfamily is an activation-inducible type I transmembrane protein receptor expressed on activated T cells, Natural Killer cells (NK), macrophages (M^), and dendritic cells (DC). Its ligand, 4-1BB-L, is a member of the tumor necrosis factor (TNF) superfamily a type II transmembrane protein that is expressed on antigen presenting cells (APC). Ligand-induced trimerization of CD137 activates multiple signaling pathways in T cells that result in transcriptional activation, enhanced T cell activation and survival. Agonistic anti-CD137 mAbs can replace the need for 4-1BB ligand-mediated receptor crosslinking either in vitro or in vivo. 4-1BB-L specific mAbs can drive cytokine production in APCs; anti-4-1BB ligand mAbs that can block receptor-ligand binding also prevent CD137-mediated T cell costimulation. However, unlike agonistic mAbs to other T cell costimulatory receptors, signaling by anti-CD137 specific mAbs can also suppress the T cellmediated immune responses. CD137 receptor-proximal and downstream signals in T cells have been largely elucidated. However, this is not the case for anti-CD137-induced immune suppression. Given that NK cells and dendritic cells express this receptor, it is not clear whether T cells are the cell targets during anti-CD137 mAb induced immune suppression. In this review we discuss CD137-mediated immune suppression and its role in regulating T-dependent B cell responses and to some extent APC function in normal, autoimmune, and tumor bearing mice.

Robert S. Mittler • Department of Surgery, Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road, Atlanta, GA 30329. Liguo Niu • Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road, Atlanta, GA 30329. Becker Hewes • Department of Pediatric Hematology and Oncology, Emory University School of Medicine, 954 Gatewood Road, Atlanta, GA 30329. Juergen Foell • Division of Pediatrics, Hematology, Oncology, and Immunology, Martin Luther University, Halle-Wittenberg, 06097 Halle, Germany.

CD137 Pathway: Immunology and Diseases. Edited by Lieping Chen, Springer, New York, 2006

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