In contrast to stimulatory effects of CD137 on CD8+ T cells in vitro and in vivo, CD137 engagement could have both stimulatory and inhibitory effects on CD4+ T cells, especially in vivo, depending on disease models used or types of immune responses mounted in vivo.
Like CD8+ T cells, CD4+ T cells upregulate CD137 upon activation, though there is evidence that CD137 expression level on CD4+ T cells is lower than that on CD8+ T cells (Taraban et al., 2002). In vitro studies show that CD137 delivers a stimulatory signal to purified polyclonal CD4+ T cells as well as antigen-specific CD4 transgenic T cells (Cannons et al., 2001; Chu et al., 1997; Gramaglia et al., 2000). Cross-linking CD137 on CD4+ T cells by CD137L or CD137 agonistic antibody increases cytokine production, proliferation and survival of T cells. As a consequence, CD4+ T cells have increased expression of the anti-apoptotic genes bcl-XL and bcl-2, as well as of cyclins D2 and E, and inhibited expression of the cyclin-dependent kinase (cdk) inhibitor p27kip1. CD137-deficient DO11.10 TCR transgenic CD4+ T cells have less cell division and are more sensitive to activation-induced cell death (AICD) when cultured with antigen in vitro (Lee et al., 2003). Furthermore, several in vivo studies also support CD137 as a stimulatory co-receptor on CD4+ T cells. CD137 agonistic mAb increases CD4+ T cell-mediated GVHD as well as its effect on CD8+ T cells (Blazar et al., 2001). In an adoptive transfer model, CD4+ transgenic (OT-II) T cells in CD137L deficient mice have minor defects during the primary response but there is a clear decrease of CD4+ T cell recall response in CD137L deficient mice, which has a similar magnitude as CD8+ T cells both in primary and recall response (Dawicki and Watts, 2004). CD4+ T cells from mice constitutively expressing CD137 on T cell showed an increased proliferative capability versus normal T cells. The proliferation and antibody response against KLH (keyhole limpet hemocyanin), a CD4+ T cell-dependent antigen, were enhanced in the CD137 transgenic mice. And CD137 transgenic mice also exhibited less apoptotic and extensive CD4+ T cell expansion, leading to an elevated contact hypersensitivity response (Kim et al., 2003). Finally, Bansal-Pakala etal., found that in vivo delivery of the CD137 signal by the agonistic antibody can restore T cell response in aged mice, which have decreased immune response due to T cell deficiency. CD137 signals promote aged CD4 T cell response in vitro and rescue the defected T cell response in aged mice (Bansal-Pakala and Croft, 2002).
In contrast to these observations, several recent studies show that CD137 agonist mAb might be an inhibitor for the CD4+ T cell-mediated immune response in vivo. An early study by Shuford and colleagues found that administration of agonistic CD137 mAb inhibits CD4+ T-dependent humoral immune responses (Shuford et al, 1997). The inhibitory effect of CD137 agonistic mAb on CD4+ T cell response has been confirmed in several autoimmune disease models by different laboratories (Foell et al., 2003; Seo et al., 2004; Sun et al., 2002a, 2002b). Experimental data to consolidate these findings is still lacking. As cells other than T cells, such as dendritic cells and natural killer cells, also express CD137, it is thus possible that CD137 signal on these cells may contribute to its suppressive effect.
And there is no report so far showing that natural interaction between CD137 and CD137L could also inhibit the CD4+ T cell-mediated immune response in vivo yet. It is also unknown whether or not CD137L is the only ligand for CD137. Recently Lee and colleagues report that CD4+ T cells response in CD137 deficient mice increase and OT-II transgenic mice deficient of CD137 had enhanced cell division and expansion in a CD137-sufficient environment (Lee et al., 2005). Taken together, these findings suggest that the CD137 signal plays a negative role in CD4+ T cell responses in vivo.
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