title: 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: 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.
authors.affiliation: Jorge Postigo, PhD, Marcos Iglesias, PhD, Luis Buelta, MD, PhD, Jesús Merino, MD: IDIVAL and Universidad de Cantabria, Santander, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Postigo
authors.affiliation: Jorge Postigo, PhD, Marcos Iglesias, PhD, Luis Buelta, MD, PhD, Jesús Merino, MD: IDIVAL and Universidad de Cantabria, Santander, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: IDIVAL and Instituto de Biomedicina y Biotecnología de Cantabria, CSIC, Universidad de Cantabria, Santander, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Álvarez
authors.affiliation: IDIVAL and Instituto de Biomedicina y Biotecnología de Cantabria, CSIC, Universidad de Cantabria, Santander, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Jesús Augustin
authors.affiliation: Jorge Postigo, PhD, Marcos Iglesias, PhD, Luis Buelta, MD, PhD, Jesús Merino, MD: IDIVAL and Universidad de Cantabria, Santander, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Buelta
authors.affiliation: Jorge Postigo, PhD, Marcos Iglesias, PhD, Luis Buelta, MD, PhD, Jesús Merino, MD: IDIVAL and Universidad de Cantabria, Santander, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Merino
authors.affiliation: IDIVAL and Instituto de Biomedicina y Biotecnología de Cantabria, CSIC, Universidad de Cantabria, Santander, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Merino
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002454:Cell Differentiation; D007376:Interleukin-2 / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C485672:Bambi protein, mouse; D019485:Bone Morphogenetic Proteins; D007376:Interleukin-2; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta