In a CIA model established in DBA/1 mice by immunization with bovine CII emulsified with CFA, Seo et al. (2004) observed a marked expansion of a unique CD8+ and IFN-y-producing regulatory T cell population which express medium level of CD11c, a surface marker highly expressed on dendritic cells, in draining lymph node and spleen of anti-CD137 treated mice. The expansion of these CD11c+CD8+ T cells required both CD137 crosslinking and antigen stimulation. When the CD11c+CD8+ T cells isolated from CII immunized and anti-CD137 treated mice were adoptively transferred into naive DBA/1 mice, they suppressed CII-specific CD4+ T cell response and the development of CIA in the recipients, suggesting their dominant inhibitory function in regulating CD4+ T cell-mediated immune responses.
CD11c+CD8+ T cells produced abundant INF-y but not regulatory cytokines such as TGF-p, IL-4 and IL-10. Blockade of INF-y in anti-CD137 treated mice reversed the suppression of CII-specific CD4+ T cell function and amelioration of CIA induced by CD137 engagement. These data imply the key role played by INF-y in the inhibition of CD4+ T cells mediated CIA (Seo et al., 2004).
To link IFN-y and the inhibition of CD4+ T cell function, Seo et al. (2004) further dissected the down stream biochemical events such as indoleamine 2,3-dioxygenase (IDO) and inducible nitric oxide synthetase (iNOS) production induced by IFN-y. They found that anti-CD137 treatment increased the levels of IDO and iNOS mRNA in CD11b+ monocytes and CD11c+ DCs, and IFN-y blockade prevents the expression of IDO and iNOS in macrophages and DCs induced by CD137 engagement. These studies suggest CD137 mediated production of IDO and iNOS by monocytes and DC is IFN-y dependent.
IDO has been shown to be an immune regulator which plays a critical role in maintaining maternal T cell tolerance to allogeneic fetuses during pregnancy (Munn et al., 1998), and in CTLA-4 mediated tolerance in transplantation and autoimmunity (Fallarino etal., 2003; Grohmann et al., 2002; Mellor et al., 2003). IDO is a tryptophan-catabolizing enzyme expressed by macrophages and other cell types; it has regulatory effects on T cells due to consuming of tryptophan which is an essential amino acids (Mellor et al., 2001; Munn et al., 1998, 1999). 1-methyl-tryptophan (1-MT) is a pharmacologic agent that competitively inhibits IDO enzyme activity (Cady and Sono, 1991). Administration of 1-MT in mice treated with anti-CD137 reversed the suppression of CIA, suggesting CD137-mediated inhibition of CIA is IDO-mediated (Seo et al., 2004).
In summary, administration of anti-CD137 in CIA model induces antigen-dependent clonal expansion of CD11c+CD8+T cells and promotes their IFN-y production. IFN-y further induces monocytes and DCs to produce IDO, which causes tryptophan catabolism and production of the metabolite kynurenine, which is thought to kill antigen-activated CD4+ T cells, leading to inhibition of autoimmune disease.
Except for CIA model, in MRL/lpr mice, anti-CD137 treatment induced massive expansion of CD8+ T cells with drastic production of IFN-y, and blockade of IFN-y reversed the reduction of autoantibody production by anti-CD137 treatment (Sun et al., 2002a). However, whether CD137-mediated suppression of SLE in MRL/lpr mice is CD8+ T cell mediated need to be defined. In another SLE animal model, NZB x NZW Fi female mice, Foell et al. (2003) observed that elimination of CD8 T cells from these mice has no effect on anti-CD137-mediated blockade of disease, suggesting CD8+ T cell-independent mechanism involved.
The inhibition of CD4+ T cell function by CD137 signaling activated CD8+ T cells has also been observed in other model. Myers et al. showed that Toll-like receptor (TLR) ligands and CD137 crosslinking massively promoted both CD4+ and CD8+ T cell clonal expansion in vivo, whereas CD137 costimulated-CD8+ T cells greatly inhibited CD4+ T cell recall responses through a type-p transforming growth factor-dependent mechanism (Myers et al., 2003). All these studies imply CD137 signaling activated CD8+ T cells could play a role in regulating CD4+ T cell function through different mechanism.
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