Overview

Co-stimulation, an integral component of immune regulation, is required for progressive T cell activation. T cell activation without co-stimulation induces anergy in which subsequent stimulation inhibits T cell responsiveness (Schwartz, 1990). Since the description of the two-signal model for T cell activation by Bretscher and Cohn (1970), understanding of the activation requirements of T cells has progressed rapidly and attained further prominence with the emergence of the CD28-B7 pathway. Several immunological ideas have since been refined, and a clearer picture of the events is slowly emerging.

Dass S. Vinay • Department of Ophthalmology, LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA Byoung S. Kwon • Department of Ophthalmology, LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA and Immunomodulation Research Center and Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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

Figure 1.1. Members of the stimulatory TNFR/TNF protein families. Although the patterns of expression of the various ligand-receptor pairs are represented in a generalized format, the actual expression patterns vary in individual cases, as some of the receptors and ligands (CD137/CD137L) can also be expressed on the same cell (see text). In most cases, the expression of CD137 or CD137L on the same type of cell was found to be functional. Unless mentioned, expression of the members of TNFR/TNF families shown is activation-induced (see text). The individual members of this superfamily are known to transmit either co-stimulatory or apoptotic signals.

Figure 1.1. Members of the stimulatory TNFR/TNF protein families. Although the patterns of expression of the various ligand-receptor pairs are represented in a generalized format, the actual expression patterns vary in individual cases, as some of the receptors and ligands (CD137/CD137L) can also be expressed on the same cell (see text). In most cases, the expression of CD137 or CD137L on the same type of cell was found to be functional. Unless mentioned, expression of the members of TNFR/TNF families shown is activation-induced (see text). The individual members of this superfamily are known to transmit either co-stimulatory or apoptotic signals.

CD137 and CD137L are an important receptor-ligand pair that belong to the tumor necrosis factor (TNF) superfamily (Vinay and Kwon, 1998; Figure 1.1). This family includes proteins that have cytoplasmic death domains and can induce apoptosis, as well as others with no apparent homology in their cytoplasmic tails. The latter group of receptors is involved in gene activation and anti-apoptotic signaling. Signal transduction by members of this family occurs through TNF receptor-associated factors (TRAFs) which counteract apoptosis via inhibition of apoptosis proteins (IAPs) and/or nuclear factor kappa B (NF-kB) (Croft, 2003).

CD137 exists as both a 30-kDa monomer and a 55-kDa homodimer (Pollok et al., 1993). It is inducible (Kwon and Weisman, 1989; Pollok et al., 1993) and is primarily expressed on activated CD4+ and CD8+ T cells, activated dendritic cells (Pollok et al., 1993) and activated NK and NKT cells (Melero et al., 1998). It is constitutively expressed on primary human monocytes, blood vessel endothelial cells, and human follicular dendritic, and CD4+CD25+ regulatory T cells (Broll et al., 2001; Kienzel and von Kempis, 2000; Lindsted et al. ,2003; McHugh et al., 2002). CD137 binds CD137 ligand (CD137L), a member of the TNF superfamily, and exists as a disulfide-linked homodimer (Goodwin et al., 1993). It is expressed on mature dendritic cells (DeBenedette et al., 1997) as well as on activated B cells and macrophages (Pollok et al., 1994). In recent years, and especially after the generation of CD137 and CD137L knockout mice (DeBenedette et al., 1999; Kwon et al., 2002), this receptor-ligand pair has provided valuable insights into T cell immunity.

Activation via CD137 generates unique biological signals. Although CD137 signaling preferentially promotes the proliferation and survival of CD8+ T cells (Shuford et al., 1997; Takahashi et al., 1999), it also supports IL-2 production by CD4+ T cells (Gramaglia et al., 2000), and prevents activation-induced cell death (Hurtado et al., 1997). CD137 has been to shown to transmit signals for potent and CD28-independent immune responses (Halstead etal., 2002; Saoulli etal., 1998). In spite of isolated reports that CD137 ligation supports Th2 responses (Chu et al., 1997), most workers believe that it amplifies Th1 responses (Kim et al., 1998). In vivo administration of agonistic anti-CD137 mAb eradicates established tumors (Melero et al., 1997), prevents the formation of autoimmune lesions (Foell et al., 2003; Seo et al., 2004; Sun et al., 2002), inhibits graft versus host disease (Kim et al., 2004), and reduces T-dependent B cells responses affecting humoral immunity (Mittler et al., 1999). Although there are few studies that relate CD137L and immune function, the available data suggests that CD137L is expressed on activated macrophages, and DC and B cells (Diehl et al., 2002; Futugawa et al., 2002; Laderach et al., 2003; Summers et al., 2001). Signaling through CD137L either by anti-CD137L mAb or by CD137 Fc/anti-Fc has been shown to promote B cell proliferation in the context of anti-^ (Pollok et al., 1994), and cytokine/chemokine production by monocytes and dendritic cells (Langstein etal., 1998; Wilcox etal., 2002).

CD137-deficient mice develop normally and are viable and fertile; they make normal humoral responses to vesicular stomatis virus, exhibit moderately reduced anti-KLH IgG2a and IgG3 isotype responses, display diminished virus-specific cytokine production and CTL activity; and have increased turnover of myeloid precursor cells in the peripheral blood, bone marrow, and spleen (Kwon et al., 2002). Recent work in our laboratory demonstrates that CD137-null mice have suboptimal NK/NKT cells and associated functions, higher levels of LPS-induced septic shock and diminished IL-4-dependent Th2 immune responses (Vinay et al., 2004). CD137L knockout mice also develop normally and have roughly normal numbers of T cells but have impaired ability to generate CTL responses to influenza virus (DeBenedette et al., 1999).

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