CD137CD137L in Health and Disease

The importance of CD137-CD137L interactions has been underscored in several experimental systems (Vinay and Kwon, 1998). Expression of CD137/CD137L has been reported in various clinical disorders. Yamada-Okabe et al. (2003) demonstrated that thyroid hormone induced CD137 expression along with caspases. Also, expression of CD137 was detected in the inflammatory tissue in Crohn's disease (Maerten et al., 2004). Interestingly, soluble forms of CD137 and CD137L were found in serum samples collected from humans with rheumatoid arthritis, and the levels of circulating CD137 and its ligand closely mirrored disease severity (Jung et al., 2004). Serum levels of soluble CD137L are also reported in patients with hematological malignancies (Salih et al., 2001). Furthermore, expression of CD137L was localized to the aortic tissue of subjects with Takayasu's arthritis (Seko et al., 2004). Likewise, Wan et al. (2004) have demonstrated expression of CD137 in both hepatocellular carcinoma and non-tumorous regions of the liver. A similar finding of CD137 expression at tumor sites was reported by Zhang et al. (2003). In addition, the peripheral blood of liver-transplant patients not only contained CD137 but its expression was correlated with clinical severity. Furthermore, both CD137 and its ligand have been detected in human neurons, astrocytes, and microglia, as well as peripheral blood samples from chronic heart failure patients (Yndestad et al., 2002) while patients with acute myocarditis and dilated cardiomyopathy had high levels of CD137L (Seko et al., 2002). Lim et al. (2002) have demonstrated CD137-like molecules in the islet-infiltrating mononuclear cells and gray matter of the brain, but the significance of such expression is unclear. In addition, CD137L expression in the hearts of mice with acute myocarditis was shown to be caused by Coxsackie Virus B3 (Seko et al., 2001). Interestingly, Salih et al. (2001) detected constitutive CD137L expression on carcinoma cells where it appeared to be functional as the cells were able to prime T cells and induce cytokine production in co-culture assays. Taken together,

Cd137 Cd137l

Figure 1.4. Consequences of CD137/CD137L signaling in immune competent cells. Co-stimulatory signals transmitted by cell-surface-derived determinants are mandatory for successful T cell activation. CD137/CD137L is an important receptor/ligand system concerned with immune regulation. Ligation of T cells either by anti-CD137 or CD137L-bearing transfectants, or soluble CD137, in the context of suboptimal doses of anti-TCR (anti-CD3) mAbs, provides strong co-stimulation leading to cell proliferation, cytokine induction, and production of immune effectors. The available evidence suggests that CD137 signaling is biased to CD8+ T cell as opposed to CD4+ T cell activation. Although CD137 has been considered a predominantly T cell antigen, other cell types (monocytes, dendritic cells etc.) also bear functional CD137 molecules. Ligation of CD137 on monocytes or dendritic cells by either anti-CD137 or soluble CD137 results in the secretion of characteristic immune modulators that further potentiate CD137/CD137L signaling. Bidirectional signals are known to exist in the case of CD137/CD137L. Thus, cross-linking of CD137L on B lymphocytes, together with ligation of the B cell receptor by anti-|i, leads to robust B cell proliferation.

Figure 1.4. Consequences of CD137/CD137L signaling in immune competent cells. Co-stimulatory signals transmitted by cell-surface-derived determinants are mandatory for successful T cell activation. CD137/CD137L is an important receptor/ligand system concerned with immune regulation. Ligation of T cells either by anti-CD137 or CD137L-bearing transfectants, or soluble CD137, in the context of suboptimal doses of anti-TCR (anti-CD3) mAbs, provides strong co-stimulation leading to cell proliferation, cytokine induction, and production of immune effectors. The available evidence suggests that CD137 signaling is biased to CD8+ T cell as opposed to CD4+ T cell activation. Although CD137 has been considered a predominantly T cell antigen, other cell types (monocytes, dendritic cells etc.) also bear functional CD137 molecules. Ligation of CD137 on monocytes or dendritic cells by either anti-CD137 or soluble CD137 results in the secretion of characteristic immune modulators that further potentiate CD137/CD137L signaling. Bidirectional signals are known to exist in the case of CD137/CD137L. Thus, cross-linking of CD137L on B lymphocytes, together with ligation of the B cell receptor by anti-|i, leads to robust B cell proliferation.

these data clearly highlight the important role of the CD137-CD137L pathway in health and disease.

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