The molecular mechanism of gc cytokine receptor expression during T cell development and differentiation remain mostly unknown. Recently, we discovered a novel post-transcriptional mechanism of gc-chain expression that resulted in the generation of soluble gc-chain proteins. We detected soluble gc (sgc) proteins in significant amounts in both normal human and mouse serum, and we found that serum sgc expression increased upon immune activation and in inflammatory conditions. To assess the role of sgc in vivo, we generated sgc transgenic mice that overexpress soluble gc in T cells. These sgc Tg mice expressed high levels of sgc in serum, and their T cells showed increased percentages of activated memory phenotype cells. However, transgenic sgc was not capable of transducing gc cytokine signals because the sgc transgene failed to restore T cell development in gc-deficient mice. Thus, sgc induces a pro-inflammatory environment but not through promoting gc signaling. Notably, we discovered that sgc proteins associated with proprietary cytokine receptors, such as IL-2Rb and IL-7Ra, even in the absence of cytokines. Such ligand-independent heterodimerization further resulted in inhibition of IL-2 and IL-7 signaling. Inhibition of IL-2 signaling, on the other hand, promoted pro-inflammatory IL-17 expression and increased the severity of inflammatory autoimmune disease. Since T cell activation induces soluble sgc production and because sgc in turn increases inflammation, we propose that sgc production is a mechanism to reinforce pro-inflammatory immune responses downstream of T cell activation. Because sgc is pro-inflammatory, it is interesting to speculate if neutralization of serum sgc expression would ameliorate inflammatory disease and dampen destructive T cell responses. Generation of sgc-specific monoclonal antibodies and assessing their effects on pro-inflammatory responses in vivo are interesting issues that we plan to pursuit, and we wish to examine the potential to utilize such antibodies as therapeutics to dampen inflammation and ameliorate disease. In parallel to soluble gc receptors, we also found soluble IL-7Ra proteins in serum of human and mice. In humans, the IL-7Ra undergoes alternative splicing, and it has been reported that alternative splicing induces the generation of soluble IL-7Ra chain proteins. This post-transcriptional event explains the presence of soluble IL-7Ra in human serum. In contrast, soluble IL-7Ra proteins have not been reported for mice. Also, there is no molecular evidence for an alternative IL-7Ra splice isoform in mice. Thus, the molecular basis of soluble IL-7Ra proteins in mouse serum remains unknown. We are currently addressing this issue using newly generate ELISA for assessing soluble IL-7Ra in mouse models. Finally, we wish to understand the regulatory mechanisms of IL-7Ra and gc expression at transcriptional level. Currently, there is no information available how gc transcription is controlled, and also there is no molecular explanation of distinct IL-7Ra expression in T cell and thymocyte subsets. We are using T cell development as a model to address this question. We had previously reported that the zinc finger protein Gfi1 controls IL-7Ra transcription specifically in CD8 lineage T cells but not in CD4 lineage cells. We have now expanded the search, and we have identified additional transcription factors that control IL-7Ra and gc cytokine receptor expression in a stage and cell-specific manner. Analyzing their roles and the molecular mechanism of regulation is currently under progress.
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