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

TGF-b is an immune regulatory cytokine central to immune homeostasis, tolerance, and autoimmunity. As a major suppressor, how SKI is involved in the fundamental roles of TGF-β in suppressing T cell function in autoimmunity and self-tolerance remains unknown. Here, we found that SKI protein was increased in activated T cells while decreased in response to exogenous and endogenous TGF-β, indicating a counter-balance role for SKI and TGF-β in activated T cells. Indeed, not only SKI deletion in T cells led to ameliorated spontaneous lethal autoimmune disease in mice with T-cell-specific deletion of TGFβRII, but also mitigated experimental autoimmune encephalomyelitis (EAE). Further investigation revealed that SKI deletion caused reduced T cell proliferation and related molecular programs even without TGF-β signaling, associating with enhanced TGF-β-related molecular program. This reveals a previously unappreciated SKI-dependent mechanism of TGF-β signaling in T cells besides current paradigm to explain how TGF-β restricts autoimmunity and bolsters tolerance.