Project description:Transforming growth factor-beta (TGF-β) restrains cytotoxic immune response to maintain self-tolerance and to promote tumor immune evasion. Yet how SMAD4, a central transcription factor component of TGF-β signaling, regulates CD8+ T cell function remains unclear. Here we have demonstrated SMAD4 played a critical role in promoting CD8+ T cell activation and cytotoxic function. SMAD4-mediated transcriptional regulation of CD8+ T cell activation and cytotoxicity is regulated by T-cell receptor (TCR) signaling pathway rather than TGF-β signaling pathway. We described a new mechanism that in TCR-mediated intracellular signal propagation, SMAD4 markedly translocated into the nucleus, upregulated genes that encoding TCR complex subunits and cytotoxic molecules in CD8+ T cells, reinforced the TCR-activation signals through a positive feedback loop. And in this signaling, SMAD4 is phosphorylated by ERK at Ser367 residue. Our study thus demonstrates an essential role of SMAD4 in promoting CD8+ T cell mediated cytotoxic immune responses.
Project description:Transforming growth factor-beta (TGF-β) restrains cytotoxic immune response to maintain self-tolerance and to promote tumor immune evasion. Yet how SMAD4, a central transcription factor component of TGF-β signaling, regulates CD8+ T cell function remains unclear. Here we have demonstrated SMAD4 played a critical role in promoting CD8+ T cell activation and cytotoxic function. SMAD4-mediated transcriptional regulation of CD8+ T cell activation and cytotoxicity is regulated by T-cell receptor (TCR) signaling pathway rather than TGF-β signaling pathway. We described a new mechanism that in TCR-mediated intracellular signal propagation, SMAD4 markedly translocated into the nucleus, upregulated genes that encoding TCR complex subunits and cytotoxic molecules in CD8+ T cells, reinforced the TCR-activation signals through a positive feedback loop. And in this signaling, SMAD4 is phosphorylated by ERK at Ser367 residue. Our study thus demonstrates an essential role of SMAD4 in promoting CD8+ T cell mediated cytotoxic immune responses.
