Effects of CD137 Engagement on CD8 T Cells in vivo

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Ligation of CD137 on naive T cells by CD137L or CD137 antibody in the absence of TCR signal does not induce detectable responses (DeBenedette et al., 1997; Pollok et al., 1993). Because naive T cells do not express detectable CD137 (Cannons etal., 2001; Pollok et al., 1995), it is thus possible that TCR is required for upregulation of CD137 on T cell surface. Studies of CD137 expression in vitro indicate that CD137 is expressed 24 h after activation with peak expression at 48-72 h (Cannons etal., 2001; Pollok etal, 1995). After immunization, however, CD137 expression by CD8+ T cells could be detected from 12 to 24 hours post-immunization and quickly disappear 36 hours after antigen challenge (Dawicki et al., 2004). Therefore, CD137 expression in vivo has a much faster on-and-off rate than in vitro . The reason for this difference is still not clear.

A fundamental understanding of the immunological functions of CD137 on T cell in vivo has been greatly improved by the use of knockout or transgenic mice. Consistent with in vitro findings, studies from various mouse models of tumors, virus infection, GVHD, and transplantation have clearly suggested that CD137

delivers a potent costimulatory signal to CD8+ T cells. The role of CD137 on tumor and viral immunity will be discussed in detail in Chapter 8. Here our discussion will mainly focus on basic immunobiology of T cell responses to antigens.

Two initial studies in 1997 demonstrated that engagement of CD137 in vivo by CD137 agonistic mAb enhances CD8 T cell proliferation and IFN-gamma production, therefore promoting acute graft versus host (GVH) disease, accelerating the cardiac and skin allograft rejection and tumor rejection (Melero et al., 1997; Shuford et al., 1997). In consistent with these findings, Cooper et al. showed that in vivo blockade of CD137 by CD137-Fc fusion protein inhibits CD8+ T cell expansion in the primary response to ovalbumin protein in adjuvant (Cooper et al., 2002). When adoptive transferred T cells are CFSE-labeled to trace cell division, administration of CD137-Fc in vivo significantly inhibits T cell division, demonstrating that CD137 functions to regulate CD8+ T cell clonal expansion by enhancing proliferation. In a tumor model, Ito et al. (2004) found that administration of CD137 mAb can enhance antitumor efficiency of dendritic cell-based vaccine. When CFSE-labeled OT-1 cells were adoptively transferred to assess the cell division by measuring CFSE profiles, the combination of anti-CD137 with DC vaccine significantly increased OT-1 T cell division in the draining lymph nodes. All these data suggest that CD137 engagement increases T cell proliferation at least partially through the enhanced cell division.

In addition to the proposed direct role of CD137 signaling in the stimulation of T cell proliferation in vivo, several studies also support an effect of CD137 on T cell survival. Administration with superantigen is a popular model to study in vivo clonal expansion and subsequent clonal contraction, which is largely mediated by activation induced cell death (AICD) of peripheral T cells. Injection of anti-CD137 mAb together with SEA only slightly affects T cell expansion in the early phase. Instead, this mAb inhibits the deletion of superantigen-activated T cells, leading to a minimal contraction phase of activated T cells during the experiments. As a result, there are nearly 10-fold the number of Ag-specific CD8 T cells in the anti-CD137-treated mice in comparison to the control mice on day 21 (Takahashi et al., 1999). A similar effect of CD137 antibody on T cell survival was also seen in a peptide vaccination model (Diehl et al., 2002). When a CFSE-labeled transgenic T cell was transferred into normal B6 mice, systemic administration of anti-CD137 mAb together with peptide did not increase T cell division. However, massive accumulation of antigen-specific transgenic T cells was only observed in mice vaccinated with peptide in combination with CD137 mAb, but not in mice that received peptide alone. Analysis of CD137L or CD137 deficient mice also suggests a predominant role for CD137 in effector T cell survival. T cells from CD137L-deficient mice show normal proliferation and cell division after viral infection. The number of antigen-specific T cells is normal at the peak of the immune response against influenza but it was clearly decreased 21 days after infection (Bertram et al., 2002). Similarly, adoptively transferred OVA-specific T cells into CD137L deficient mice also show normal T cell expansion but defects in the maintenance of T cell survival (Dawicki and Watts, 2004). Thus, CD137 signaling may be involved in promoting the development of memory T cells from CD8+ effector T cells.

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