Objective 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). Methods 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. Results 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. Conclusion 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.

The inhibition of apoptotic cell death in T cells through the dysregulated expression of BCL2 family members has been associated with the protection against the development of different autoimmune diseases. However, multiple mechanisms were proposed to be responsible for such protective effect. The purpose of this study was to explore the effect of the T-cell overexpression of BCL2A1, an anti-apoptotic BCL2 family member without an effect on cell cycle progression, in the development of collagen-induced arthritis. Our results demonstrated an attenuated development of arthritis in these transgenic mice. The protective effect was unrelated to the suppressive activity of regulatory T cells but it was associated with a defective activation of p38 mitogen-activated protein kinase in CD4+ cells after in vitro TCR stimulation. In addition, the in vitro and in vivo TH17 differentiation were impaired in BCL2A1 transgenic mice. Taken together, we demonstrated here a previously unknown role for BCL2A1 controlling the activation of CD4+ cells and their differentiation into pathogenic proinflammatory TH17 cells and identified BCL2A1 as a potential target in the control of autoimmune/inflammatory diseases.