SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8⁺ T cell cytotoxic function

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 Ser³⁶⁷ residue following TCR activation. Our study thus demonstrates a critical yet unexpected role of SMAD4 in promoting CD8⁺ T cell-mediated cytotoxic immunity.