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

Objective. Transforming growth factor beta (TGF beta) plays a prominent role in the establishment of immunologic tolerance, and mice lacking TGF beta 1 die of multiorgan inflammation early in life. TGF beta 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, TGF beta 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 TGF beta 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 TGF beta and fixed the appropriate intensity level of TGF beta signaling in CD4+ cells. Its deficiency protected mice against the development of CIA by a Treg cell-and TGF beta-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 TGFb-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 TGFb and IL-2 signaling strength, regulates the differentiation of CD4+ lymphocytes and the development of autoimmune arthritis.