CD137 (4-1BB) is an inducible T cell co-stimulatory receptor and belongs to tumor necrosis factor receptor superfamily (TNFRSF9). In addition to its expression on activated T cells (Kwon and Weissman, 1989; Pollok et al., 1993), it is also expressed on other lymphocytes, including activated NK cells (Melero et al., 1998), NK T cells (Kwon et al., 2000) and CD4+CD25+ regulatory T cells (Gavin et al., 2002; McHugh et al., 2002), as well as myeloid cells, such as monocytes, neutrophils, and dendritic cells (Futagawa et al., 2002; Heinisch et al., 2000; Kwon et al., 1997; Wilcox et al., 2002a). CD137L (4-1BBL), a member of TNF superfamily (TNFSF9), has been detected on professional antigen presenting cells (APCs) such as B cells, macrophages, and dendritic cells (Alderson et al., 1994; Goodwin et al., 1993; Pollok et al., 1994). This type of expression pattern indicates CD137/CD137L interactions may play a role in multiple steps in various innate and adaptive immune responses.

It has been shown that CD137 engagement with either CD137L or agonistic monoclonal antibodies (mAbs) against CD137 together with TCR signaling results in increased T cell proliferation, cytokine production and prolonged CD8+ T cell survival (Hurtado etal., 1997;Pollok etal., 1993; Takahashi etal., 1999).In addition, experiments performed in both CD137 and CD137L-deficient mice suggest CD137 costimulation may play an important role in T cell-mediated immune responses (Blazar et al., 2001; DeBenedette et al., 1999; Tan et al., 1999, 2000). In accordance with its costimulatory function, agonist mAbs against CD137 have been shown to promote T cell cytolytic activity leading to increased allograft rejection (Shuford et al. ,1997) and tumor eradication (Melero et al. ,1997), broaden CD8+ T cell responses in viral immunity (Halstead et al., 2002). CD137/CD137L interaction deficit prevents the development of autoimmune disease in some animal models (Seo et al., 2003, 2004). These studies support the notion that CD137 signaling increases T cell function which may enhance immunity against tumors and infection, and CD137/CD137 pathway may participate in the pathogenesis of autoimmune disease.

Yonglian Sun and Yang-Xin Fu • The Department of Pathology and Committee in Immunology, The University of Chicago, Chicago, Illinois, USA.

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

However, recent studies indicate a diametric outcome of CD137 signaling. Agonistic mAbs against CD137 that promoted tumor rejection in mice were also able to suppress T-dependent humoral immunity (Mittler et al., 1999) and ameliorate multiple organ-specific and systemic autoimmune diseases (Foell etal., 2003, 2004; Seo et al., 2004; Shao et al., 2005; Sun et al., 2002a, 2002b). In support of the possible regulatory role of CD137 signaling in T cell response, it has been shown that CD137-deficient T cells are hyperresponsive to mitogens compared with WT T cells (Kwon et al., 2002). These studies strongly suggest that CD137 signaling is capable of modulating immune responses differentially in vivo. Here, we review recent studies on endogenous and exogenous CD137 signal in the regulation of T cell-mediated autoimmune responses especially the application of agonistic mAbs against CD137 in different autoimmune disease models and the mechanisms involved.

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