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Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance

Hiroyuki Takaba1, Yasuyuki Morishita2, Yoshihiko Tomofuji3

  • 1Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Takayanagi Osteonetwork Project, Exploratory Research for Advanced Technology Program, Japan Science and Technology Agency (JST), Tokyo 113-0033, Japan.

Cell
|November 7, 2015
PubMed

Self-tolerance to immune reactions is established via promiscuous expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), leading to the elimination of T cells that respond to self-antigens. The transcriptional regulator Aire has been thought to be sufficient for the induction of TRAs, despite some indications that other factors may promote TRA expression in the thymus. Here, we show that the transcription factor Fezf2 directly regulates various TRA genes in mTECs independently of Aire. Mice lacking Fezf2 in mTECs displayed severe autoimmune symptoms, including the production of autoantibodies and inflammatory cell infiltration targeted to peripheral organs. These responses differed from those detected in Aire-deficient mice. Furthermore, Fezf2 expression and Aire expression are regulated by distinct signaling pathways and promote the expression of different classes of proteins. Thus, two independent factors, Fezf2 and Aire, permit the expression of TRAs in the thymus to ensure immune tolerance.

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