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

T helper 17 (T(H)17) cells are critically involved in host defence, inflammation, and autoimmunity(1-5). Transforming growth factor beta (TGF beta) is instrumental in T(H)17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGF beta enables T(H)17 cell differentiation remains elusive. Here we reveal that TGF beta enables T(H)17 cell differentiation by reversing SKISMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor gamma t (ROR gamma t). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF beta signalling in a ROR gamma t-dependent manner. Ectopic SMAD4 expression suppresses ROR gamma t expression and T(H)17 cell differentiation of SMAD4-deficient T cells. However, TGF beta 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 TGF beta 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, TGF beta-induced disruption of SKI reverses SKISMAD4-mediated suppression of ROR gamma t to enable T(H)17 cell differentiation. This study reveals a critical mechanism by which TGF beta controls T(H)17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating T(H)17-related diseases.