Zellspezifische TGFß Antworten: Zelluläre und molekulare Ursachen der Autoimmunerkrankung in Smif-defizienten Mäusen
Final Report Abstract
TGFβ is a pluripotent immunosuppressive cytokine controlling proliferation, differentiation and activation of immune cells in a context specific manner. Smif was originally identified as a coactivator of TGFβ-responsive genes in cell lines. Yet, the functions of Smif in vivo are not known. To explore these roles we generated a Smif-deficient mouse strain. Smifko embryonic fibroblasts exhibit greatly reduced transcription from TGFβ-responsive reporter elements, which was rescued by the reexpression of Smif. Likewise, T cells from Smif-deficient mice showed defective TGFβ responses including impaired inhibition of proliferation in vitro. Consistently, lack of Smif resulted in spontaneous T cell activation in vivo characterized by upregulation of CD25, CD69 and CD44 and a decrease in CD62L. In contrast, B cell function was not impaired. Finally, Smifko mice develop a lethal autoimmune disease involving multiple organs. Thus, our results identify Smif as a non-redundant cell type specific regulator of TGFβ signaling that is essential to prevent autoimmunity.
