Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation

TGFβ signalling regulates T helper 17 (TH17) cell differentiation by reversing SKI–SMAD4-mediated suppression of RORγt, revealing a potential therapeutic target for treating TH17-related diseases. SKI-SMAD4 holds licence to differentiate Yisong Wan and colleagues describe a novel mechanism by which transforming growth factor beta (TGFβ) regulates differentiation of T helper 17 (T H 17) cells. TGFβ and interleukin-6 (IL-6) are required for induction of the master transcription factor RORγt, but too much TGFβ is inhibitory. In this study the authors show that SMAD4—a key signal transducer activated by TGFβ receptor ligation—forms a complex with the transcriptional repressor SKI, and together they suppress transactivation of RORγt and T H 17 cell differentiation. T helper 17 (T H 17) cells are critically involved in host defence, inflammation, and autoimmunity 1 , 2 , 3 , 4 , 5 . Transforming growth factor β (TGFβ) is instrumental in T H 17 cell differentiation by cooperating with interleukin-6 (refs 6 , 7 ). Yet, the mechanism by which TGFβ enables T H 17 cell differentiation remains elusive. Here we reveal that TGFβ enables T H 17 cell differentiation by reversing SKI–SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into T H 17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and T H 17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and T H 17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and T H 17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI–SMAD4-mediated suppression of RORγt to enable T H 17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls T H 17 cell differentiation and uncovers the SKI–SMAD4 axis as a potential therapeutic target for treating T H 17-related diseases.