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. 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. J. Postigo, M. Iglesias, P. Álvarez, J.J. Augustin, L. Buelta, J. Merino and R. Merino. 2016-05-31T22:00:00Z<p>​<strong class="ms-rteFontSize-2" style="text-align:justify;">Abstract:</strong></p><p style="text-align:justify;"><span class="ms-rteFontSize-2"><em>Objective.</em>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<sup>+</sup>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<sup>+</sup>cells and in the control of immunologic tolerance in mice with collagen-induced arthritis (CIA).</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2"><em>Methods.</em>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.</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2"><em>Results.</em>BAMBI was induced after activation by TGFβ and fixed the appropriate intensity level of TGFβ signaling in CD4<sup>+</sup>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<sup>+</sup>cells and modulated Treg cell and Th17 cell differentiation both in vitro and in vivo.</span></p><p style="text-align:justify;"><em class="ms-rteFontSize-2">Conclusion.</em><span class="ms-rteFontSize-2">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</span><sup class="ms-rteFontSize-2">+</sup><span class="ms-rteFontSize-2">lymphocytes and the development of autoimmune arthritis.</span><br></p><p><span class="ms-rteFontSize-2"><a href="https://www.ncbi.nlm.nih.gov/pubmed/26714180">​Arthritis Rheumatol. 2016, 68:1551-1562.doi: 10.1002/art.39557. </a></span></p>164