CD137 is an activation inducible member of the TNFR superfamily and is found on activated thymocytes, T cells (Kwon et al, 1994; Pollok et al., 1993; Schwarz et al, 1995), and NK cells (Melero et al, 1998b). It has recently been found on granulocytes (Heinisch et al., 2000), eosinophils (Heinisch et al.,
2001), macrophages (Kienzle and von Kempis, 2000; Langstein et al., 1998), DC (Futagawa et al., 2002; Pauly et al., 2002; Summers et al., 2001; Wilcox et al.,
2002), and within the intra-tumor vasculature of patients with metastatic disease (Broll et al., 2001). The cognate ligand for CD137, 4-1BB ligand, a member of the TNF superfamily (Goodwin et al., 1993; Zhou et al., 1995), is constitutively expressed at low levels on B cells, increases with B cell activation, and can be activation induced on macrophages and DC following CD40 or LPS mediated APC activation. The kinetics of expression of CD137 varies depending upon the experimental system under study. For instance, CD137 expression is evident within 24 hours of anti-CD3/anti-CD28 mediated in vitro activation of mouse T cells, or in acute graft versus host disease (GVHD). We find that CD8 T cells achieve maximal expression of CD137 within 24-36 hours following anti-CD3 induced in vitro activation, whereas CD4 T cells tend to lag behind. However, within 48 hours both subsets reach equivalent levels of expression (Mittler et al., 2004). In LCMV infected mice we find no evidence of CD137 expression on either CD4 or CD8 T cells until 72 hours post-infection (unpublished observations) and the appearance of CD137 is first observed on splenic and lymph node CD4 T cells in these mice. In contrast, expression of CD137 on CD8 T cells occurs much more rapidly in superantigen (sAg) injected mice and can be seen within 6-12 hours after injection of sAg (Takahashi et al., 1999). The difference in the rate of expression most likely reflects, or is at least dependent upon the kinetics of induction of prerequisite activation events such as the expression of CD154 on T cells and upregulation of CD80 and CD86 on antigen presenting cells.
Crosslinking CD137 with anti-CD137 mAbs, soluble 4-1BB ligand fusion proteins, or 4-1BB ligand transfected cell lines induces T cell costimulation in antigen or mitogen activated T cells (DeBenedette et al., 1995; Shuford et al., 1997). Whereas costimulation of T cells by anti-CD28 preferentially activates CD4 T cells, we have found that anti-CD137 mAbs preferentially induces CD8+ T cell activation (Shuford et al., 1997) and drives their production of IFN-y (Shuford et al., 1997) and TNF-a (our unpublished observations). However, others have not found this to be the case (Cannons et al., 2001) and the discrepancy between these two reports has not been resolved. In mice, injection of anti-CD137 mAbs resulted in accelerated rejection of skin or cardiac allografts and exacerbated acute GVHD (Shuford et al., 1997).
The underlying cellular and molecular events by which CD137-mediated T cell costimulation regulates the function of the immune system are rapidly coming into focus (Watts, 2005). Furthermore, the potential for targeting the CD137 signaling pathway in treating diseases such as autoimmunity and cancer seems promising (Foell et al., 2003, 2004; Melero et al, 1997; Seo et al, 2004; Sun et al., 2002). In the following sections of this review we describe the effects of anti-CD137 treatment of mice and how these antibodies regulate T-dependent humoral immunity. We will also discuss how B cells may suppress the development of anti-tumor immunity and how this condition can be reversed with anti-CD137 mAbs. The studies reported in this review were based on our early studies of anti-CD137 mediated suppression of humoral immunity in mice (Mittler et al., 1999) and the anti-tumor properties of anti-CD137 mAbs (Melero et al., 1997, 1998a).
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