Bone morphogenetic protein and activin membrane-bound inhibitor, a transforming growth factor β rheostat that controls murine treg cell/Th17 cell differentiation and the development of autoimmune arthritis by reducing interleukin-2 signaling

Abstract

[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.