Smad-independent pathways in CD4+ T cells from BAMBI-KO mice. Consequently, these cells also expressed higher levels of CD25 than those from wild-type mice; this increase, which was prevented by a Smad3-specific inhibitor, potentiated IL-2 signalling to promote TREG-cell differentiation. In BAMBI-KO mice, the incidence and severity of collagen-induced arthritis (CIA) was lower than in wild-type mice, in association with a significant increase in the number of CD25+ TREG cells. TREG cell depletion abrogated protection against CIA and was accompanied by an increase in the number of TH17 cells. Inhibition of TGF-β also increased the severity of CIA. By regulating the strength of TGF-β and IL-2 signalling, BAMBI controls CD4+ cell differentiation and, in turn, immunological tolerance. Perhaps not surprisingly, Postigo et al. are currently analysing the therapeutic potential of BAMBI inhibition in different autoimmune/inflammatory diseases.