SKI is critical to counter TGF-β signaling to promote T cell function and autoimmunity.

Transforming growth factor-β (TGF-β) is central to suppressing T cell function to maintain tolerance and immune homeostasis. The current TGF-β signaling paradigm is however inadequate in explaining how TGF-β controls T cell function. Here, we found a previously unappreciated, SKI-dependent mechanism of TGF-β signaling to better explain how TGF-β restricts T cell function to bolster tolerance. We found that SKI protein was up-regulated in activated T cells and down-regulated in response to TGF-β, indicating a reciprocal relationship between SKI and TGF-β in controlling T cell function. T cell-specific SKI deletion ameliorated spontaneous lethal autoimmunity due to T cell-specific TGFβRII deletion and mitigated MOG/CFA-induced experimental autoimmune encephalomyelitis. SKI was required for activation-induced T cell function and related molecular programs. Therefore, inhibition of TGFβR not only results in the loss of Smad-dependent function but, more importantly, leads to the gain of SKI-dependent activity, which is essential for T cell-mediated autoimmunity. A critical mechanism underlying TGF-β-mediated suppression of T cell function is overcoming SKI activity.