Transforming growth factor β (TGFβ) plays a prominent role in the establishment of immunologic tolerance, and mice lacking TGFβ1 die of multiorgan inflammation early in life. TGFβ controls the differentiation of CD4+ lymphocytes into Treg cells or proinflammatory Th17 cells. Although this dual capacity is modulated by the presence of additional cytokines around the activated cells, TGFβ also dissociates Th17/Treg cell differentiation in a dose‐dependent manner by mechanisms still unknown. The purpose of this study was to explore the contribution of bone morphogenetic protein and activin membrane–bound inhibitor (BAMBI) to the modulation of TGFβ activity during the differentiation of CD4+ cells and in the control of immunologic tolerance in mice with collagen‐induced arthritis (CIA).

The in vitro and in vivo Treg cell and Th17 cell differentiation and the development of CIA were compared in wild‐type mice and BAMBI‐deficient mice.

BAMBI was induced after activation by TGFβ and fixed the appropriate intensity level of TGFβ signaling in CD4+ cells. Its deficiency protected mice against the development of CIA by a Treg cell– and TGFβ‐dependent mechanism. Mechanistically, BAMBI was found to regulate CD25 expression and interleukin‐2 (IL‐2) signaling in Treg cells and in IL‐2– and/or TGFβ‐activated CD4+ cells and modulated Treg cell and Th17 cell differentiation both in vitro and in vivo.

Taken together, the results indicate that BAMBI is a component of a rheostat‐like mechanism that, through the control of TGFβ and IL‐2 signaling strength, regulates the differentiation of CD4+ lymphocytes and the development of autoimmune arthritis.