Although IL-15 is known to be a T cell growth factor, the function in T cells of IL-15Rα, its high affinity receptor, remains unclear. We found that murine IL-15Rα−/− CD4+ T cells hyperproliferated in response to TCR stimulation, in vitro and in vivo, and displayed a lower TCR activation threshold than wild-type CD4+ T cells. TCR-induced activation of Zap70 and of the phospholipase C-γ1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Rα−/− CD4+ T cells. This in turn led to earlier IL-2Rα induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Rα−/− CD4+ T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Rα, and division in wild-type CD4+ T cells. These results reveal IL-15Rα to be a negative regulator for CD4+ T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.
Japanese encephalitis virus (JEV) is one of approximately 70 flaviviruses, frequently causing symptoms involving the central nervous system. Mutations of its genomic RNA frequently occur during viral replication, which is believed to be a force contributing to viral evolution. Nevertheless, accumulating evidences show that some JEV strains may have actually arisen from RNA recombination between genetically different populations of the virus. We have demonstrated that RNA recombination in JEV occurs unequally in different cell types. In the present study, viral RNA fragments transfected into as well as viral RNAs synthesized in mosquito cells were shown not to be stable, especially in the early phase of infection possibly via cleavage by exoribonuclease. Such cleaved small RNA fragments may be further degraded through an RNA interference pathway triggered by viral double-stranded RNA during replication in mosquito cells, resulting in a lower frequency of RNA recombination in mosquito cells compared to that which occurs in mammalian cells. In fact, adjustment of viral RNA to an appropriately lower level in mosquito cells prevents overgrowth of the virus and is beneficial for cells to survive the infection. Our findings may also account for the slower evolution of arboviruses as reported previously.
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