Soluble forms of CD137 (sCD137) and CD137 ligand exist. Soluble CD137 is generated by differential splicing and released by activated T cells (Michel et al., 1998). Levels of sCD137 are enhanced in sera of autoimmune, leukemia and lymphoma patients (Furtner et al., 2005; Jung et al., 2004; Michel et al., 1998; Sharief, 2002). Release of sCD137 does not correlate with proliferation but rather with activation induced cell death (Michel and Schwarz, 2000), implying that sCD137 forms a negative feedback loop to reduce further activation through membrane-bound CD137 and to prevent activation induced cell death. Indeed in soluble forms of CD137 proteins antagonize the costimulatory activities of the membrane-bound CD137 and reduce immune activity (DeBenedette et al., 1995; Hurtado etal., 1995). It has been demonstrated in the case ofmonocytes (Langstein and Schwarz, 1999; Langstein etal., 1998; 1999) and T cells (Schwarz etal., 1996) that soluble CD137 protein is not able to crosslink CD137 ligand and to initiate signaling. Soluble forms of CD137 seem therefore to antagonize CD137 as well as CD137 ligand signaling.
Soluble CD137 ligand is generated by proteolytic cleavage and levels of sCD137 ligand are enhanced in sera of patients suffering from hematological malignancies and autoimmune disease (Salih et al., 2001; Jung et al., 2004; Salih etal., 2004). In contrast to sCD137 which seems to be purely antagonistic, sCD137 ligand is active and can provide costimulation to T cells (Salih et al., 2001). This implies that sCD137 ligand only inhibits reverse signaling through CD137 ligand while initiating signaling through CD137.
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