Significance of Reverse Signal Transduction for the Biology of the CD137 Receptor Ligand System

Herbert Schwarz

CD137 is a member of the TNF receptor family and it has originally been identified as a potent T cell costimulatory molecule. Recently, it has become evident that CD137 signals can also inhibit T cell activity under certain conditions.

The CD137 receptor/ligand system has the ability to signal bidirectionally. CD137 ligand is also expressed as a cell membrane protein and it can also transduce signals into the cells it is expressed on, referred to as reverse signaling. The signals through CD137 ligand are activating or costimulatory for antigen presenting cells (APC). Together with CD137, which can deliver costimulatory signals to T cells, the CD137 receptor/ligand pair can therefore form a potent proinflammatory system enhancing immune reactions by stimulating APC as well as T cells. CD137 ligand signals, however, negatively regulate T cell proliferation and survival, and it is possible that this activity of CD137 ligand participates in the termination of immune responses.

The bidirectional signaling capacity allows the CD137 receptor/ligand system to mediate extensive crosstalk between immune cells and between immune and non-immune cells.

CD137 (4-1BB, induced by lymphocyte activation, ILA) is a member of the tumor necrosis factor (TNF) receptor family (Kwon and Weissman, 1989; Schwarz et al., 1993). CD137 has originally been identified as a potent T cell costimulatory molecule and a promising target for immunotherapy of cancer (Melero et al., 1997). Recent evidence also demonstrates a role for CD137 signaling in T cells for inhibiting immune responses and autoimmune disease (Foell et al., 2003; 2004). The other chapters of this book and several recent reviews provide a comprehensive overview over the various activities of CD137 signaling on immune functions and their potential therapeutic applications (Al-Shamkhani, 2004; Croft, 2003; Kwon et al., 2000; Sica and Chen, 2000).

Interaction of CD137 with CD137 ligand, however, not only initiates a signal into the CD137-expressing cell but also into the CD137 ligand-expressing

Herbert Schwarz • Department of Physiology, National University of Singapore, 2 Medical Drive, MD 9, Singapore 117597

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

(-C3CD137 ligand o^CDm

Figure 3.1. Schematic representation of bidirectional signaling mediated by the CD137 recep-tor/ligand system between a monocyte and an activated T cell. In this case both cells receive activating signals, through CD137 ligand and CD137, respectively.

(-C3CD137 ligand o^CDm

Figure 3.1. Schematic representation of bidirectional signaling mediated by the CD137 recep-tor/ligand system between a monocyte and an activated T cell. In this case both cells receive activating signals, through CD137 ligand and CD137, respectively.

cell. In other words, the CD137 receptor/ligand system can signal bidirection-ally (Figure 3.1). Signal transduction through the ligand is referred to as reverse signaling. The CD137/CD137 ligand system shares the ability of bidirectional signal transduction and reverse signaling with many other members of the TNF receptor and TNF families (Arens et al., 2004; Eissner et al., 2004). Reverse signaling in the TNF family is possible because most of its members are expressed as membrane proteins with cytoplasmic domains (Gravestein and Borst, 1998; Lotz et al., 1996). The designation as ligands for these molecules is based on historical reasons but in functional terms they would more aptly be described as counter receptors.

For the CD137 receptor/ligand system reverse signal transduction, that is signaling through CD137 ligand is an activity which has received far less attention than signal transduction through CD137 and its initiated biological activities. This chapter aims to summarize and review what is known about signal trans-duction through CD137 ligand and that side of the CD137/CD137 ligand biology (Table 3.1). In the following, the description of the effects of CD137 ligand signaling is organized according to the cell types involved.

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