Characterization of murine soluble CD137 and its biological activities

Abstract

CD137 is a member of the tumor necrosis factor receptor family, and is involved in the regulation of a range of immune activities. Soluble forms of CD137 may antagonize membrane-bound CD137 and regulate host immune responses. Here we report in this study that soluble CD137 can be generated by differential splicing and is mainly released by activated T cells. Other immune cells that express soluble CD137 include Treg and dendritic cells. Expression levels of soluble CD137 correlate with those of membrane-bound CD137 in most cases except for DC. Soluble CD137 exists as a trimer and a higher order multimer and can bind to CD137 ligand, suggesting it has antagonistic effect on membrane-bound CD137. Levels of soluble CD137 correlate with activation induced cell death and depletion of soluble CD137 results in increase of IL-10 and IL-12. Soluble CD137 is present in sera of mice with autoimmune disease but is undetectable in sera of healthy mice.Besides its expression in immune cells, CD137 was also found to be expressed in certain cancer cells. The correlation of CD137 expression and malignancy points to a selection advantages that CD137 expression provides to the tumor. The potential role of CD137 as a cancer neoantigen was characterized in this study. Using cell lines which overexpress CD137, it was found that CD137 signaling in B cell lymphoma A20 induces activation of the NF-N:B pathway, which is accompanied by changes of cell morphology and IL-10 production. However, the effect of CD137 was not observed in vivo, as no significant difference could be found between the growth rates of tumors formed by CD137-expressing and control A20 cells. Further studies will be needed to characterize the role of CD137 in tumorigenesis and possible antagonistic effect of soluble CD137 in this process.