Abstract TGFβ is involved in both Treg and Th17 differentiation via its induction of Foxp3 and RORγt. The oncogene c-ski regulates TGFβ function by inhibiting SMAD2/3 from both binding to SMAD4 and to DNA, repressing the transcription of TGFβ-inducible genes. Previously, we have shown that the absence of ski in medullary thymic epithelial cells (mTECs) limits cellular growth due to unchecked TGFβ signaling. Given that central role of Treg and Th17 cells in the development of autoimmune disease, we explored the role of Ski and TGFβ signaling in T cell function and differentiation. We demonstrate that the absence of Ski in CD4+ T cells leads to amplified TGFβ sensitivity as shown by increased Th17 differentiation at low levels of TGFβ in vitro. Additionally, Foxp3CreSkifl/flT cells polarized in the presence of TGFβ and IL-2 in vitro lead to increased Treg conversion in culture, suggesting that Ski may also play a role in Treg stability. To determine the role of Ski in an autoimmune disease model in vivo, we transferred Ski-deficient or WT naïve CD4+ T cells into Rag1−/− host mice. Ski-deficient T cells induced significantly greater colitis disease severity that was mirrored by increases in double-producing IL-17A and IFNγ pathogenic CD4 T cells. In conclusion, we have shown that Ski functions as a modifier of TGFβ signaling in CD4+ T cells and can directly influence the outcome of autoimmune disease pathogenesis.