SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8 <sup>+</sup> T cell cytotoxic function
Xinwei Liu, Jing Hao, Peng Wei, Xiaohong Zhao, Qiuyan Lan, Lu Ni, Yongzhen Chen, Xue Bai, Ling Ni, Chen Dong
Abstract
Transforming growth factor–β is well known to restrain cytotoxic T cell responses to maintain self-tolerance and to promote tumor immune evasion. In this study, we have investigated the role of SMAD4, a core component in the TGF-β signaling pathway, in CD8 + T cells. Unexpectedly, we found that SMAD4 was critical in promoting CD8 + T cell function in both tumor and infection models. SMAD4-mediated transcriptional regulation of CD8 + T cell activation and cytotoxicity was dependent on the T cell receptor (TCR) but not TGF-β signaling pathway. Following TCR activation, SMAD4 translocated into the nucleus, up-regulated genes encoding TCR signaling components and cytotoxic molecules in CD8 + T cells and thus reinforced T cell function. Biochemically, SMAD4 was directly phosphorylated by ERK at Ser 367 residue following TCR activation. Our study thus demonstrates a critical yet unexpected role of SMAD4 in promoting CD8 + T cell–mediated cytotoxic immunity.