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Abstract:
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The aging process is strongly associated with decreased activity in the immune system . Dysregulation of T -lymphocyte function , such as reduced proliferation , is one problem faced by most elder people , which prevents them from successfully dealing with exogenous pathogens . Effective regulation of T -lymphocyte activity depends on the proper and prompt transduction of both positive and negative signals within Tlymphocytes and reflects the balance between positive and negative effects . Decline of positive signaling in aging has been studied and reported , while mechanisms concerning up -regulation of negative signaling with age and its role in immune senescence are still unclear . Cbl -b , an E3 ubiquitin ligase , was studied by our lab since it regulates the ubiquitin process , a protein modification process that has suppressive effects on signaling pathways . We first determined the reaction of Cbl -b to different stimuli in young rat splenic T -lymphocytes , and showed that there is a decrease in Cbl -b protein expression upon CD28 stimulation and such protein degradation is proteasome -dependent only . We also showed the mechanism of Cbl -b expression regulation involves the intracellular movement of Nedd4 toward Cbl -b and an up -regulation of Nedd4 expression . Then we proved that in old splenic T -lymphocytes , decreased proteasome activity was unable to down -regulate the Cbl -b protein . High levels of Cbl -b in old T -lymphocytes are functional in preventing PI3K activity and are associated with reduced T -lymphocyte proliferation upon regular stimulation . T -lymphocytes from old Cbl -b knock -out mice show similar proliferative reaction to CD3 stimulation as T -lymphocytes from young wild -type , which establishes the causeeffect relationship between sustained Cbl -b expression and decreased T -lymphocyte proliferation . In summary , these data suggest a unique role of Cbl -b in regulating Tlymphocyte signal transduction and provide critical preliminary data for extending Cbl -b studies into other fields , such as carcinogenesis . |