A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

Transforming growth factor-beta (TGF-β) suppresses Tcell function to maintain self-tolerance and to promote tumor immune evasion. Yet how Smad4, a transcription factor component of TGF-β signaling, regulates Tcell function remains unclear. Here we have demonstrated an essential role for Smad4 in promoting Tcell function during autoimmunity and anti-tumor immunity. Smad4 deletion rescued the lethal autoimmunity resulting from transforming growth factor-beta receptor (TGF-βR) deletion and compromised T-cell-mediated tumor rejection. Although Smad4 was dispensable for Tcell generation, homeostasis, and effector function, it was essential for Tcell proliferation after activation invitro and invivo. The transcription factor Myc was identified to mediate Smad4-controlled Tcell proliferation. This study thus reveals a requirement of Smad4 for T-cell-mediated autoimmunity and tumor rejection, which is beyond the current paradigm. It highlights a TGF-βR-independent role for Smad4 in promoting Tcell function, autoimmunity, and anti-tumorimmunity.