Dendritic cells (DCs) are among the most potent antigen-presenting cells for the priming of T cell responses, thus contributing to adaptive immunity. In addition, DCs also participate in innate immunity. First, DCs express abundant molecules which are responsible for the activation of NK cells (Degli-Esposti and Smyth, 2005). Second, DCs can release an array of cytokines, upon activation, which are important in the regulation of immune responses, including innate immunity (Steinman et al., 2005). Third, activated DCs are shown to directly kill tumor cells, largely due to their capacity to release TNF-a or to suppress the growth of tumor cells in vitro by a poorly understood "cytostasis" mechanism (Chapoval et al., 2000).
Freshly isolated mouse splenic DCs and bone marrow-derived DCs express CD137 on the cell surface (Futagawa et al., 2002; Wilcox etal., 2002). In addition, the soluble form of CD137 could also be detected in DC culture (Wilcox et al., 2002). This may represent an alternative splicing form of CD137 and a potential decoy receptor. Co-incubation of CD137L transfected cells with DCs induces secretion of IL-6 and IL-12 (Futagawa et al., 2002; Wilcox et al., 2002). Furthermore, splenic DCs isolated from mice that were given a CD137 mAb were better able to stimulate proliferation of antigen-specific T cells when compared to DCs isolated from mice that had received a control led antibody (Wilcox et al., 2002). Collectively, this data has implicated CD137 as an important receptor capable of stimulating functional maturation of DCs.
In addition to constitutive expression of CD137, DCs could also express CD137L, which has been shown to contribute to T cell costimulatory function (see Chapter 3). Therefore, interaction between CD137 and CD137L may represent one of molecular mechanisms of DC-DC interaction and may be a new mode of DC activation. IL-12 production by anti-CD40-stimulated DCs could be partially inhibited by an anti-CD137L mAb (Futagawa et al., 2002), suggesting a role of CD137 pathway in the regulation of DC-DC interaction.
In addition to the role of CD137 in the activation of DCs in cell culture system, administration of CD137 mAb in RAG-1-deficient mice was shown to enhance the ability of CD137-expressing splenic DCS isolated from these mice to stimulate T cell proliferation (Wilcox et al., 2002). These results suggest that activation of DCs through CD137 modulate DC function in vivo. This experiment also shows that CD137 engagement can directly activate DCs independently on T and B cells. The roles of endogenous CD137 signals through DCs in the modulation of DC function have also been implicated in several studies. Administration of CD137Ig as a blocking agent impaired the accumulation of recipient DCs within mouse spleen in an intestinal allograft transplantation model (Wang et al., 2003). In a collagen-induced arthritis mouse model, administration of agonist CD137 mAb inhibited the development of rheumatoid arthritis in a susceptible DBA/1 model, accompanied with accumulation of indoleamine 2,3-dioxygenase in CD11b monocytes andCD11c+ DC (Seo etal., 2004). One caveat is, that although these findings could be interpreted as direct engagement of CD137 on DC, it is also possible that this is a consequence of T cell activation by CD137 antibody. Therefore, definitive experiments to address this issue have yet to be completed.
In summary, although current experimental results support stimulatory function of CD137 signal for functional maturation of DCs, our knowledge in this area is very limited. For example, the DCs have multiple subsets that possess diverse immunological functions. The DC subset used in current studies is myeloid DCs and the expression pattern and functionality in other subsets such as the plasma-toid DC has not yet been explored. In addition, DCs express a large number of molecules with diverse functions; it is possible that the functions of CD137 signal may be replaceable by other molecules. These issues are yet to be addressed.
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