title: Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells.
abstract: The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4(+) T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses.
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Maxime
authors: M
authors: Dhainaut
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Caroline
authors: C
authors: Coquerelle
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Sophie
authors: S
authors: Uzureau
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Julie
authors: J
authors: Denoeud
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Valérie
authors: V
authors: Acolty
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Guillaume
authors: G
authors: Oldenhove
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium Center for Microscopy and Molecular Imaging, Gosselies, Belgium.
authors: Adrien
authors: A
authors: Galuppo
authors: Institute of Infection Immunology, Hannover, Germany.
authors: Tim
authors: T
authors: Sparwasser
authors: Medical School, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Kris
authors: K
authors: Thielemans
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.
authors: Etienne
authors: E
authors: Pays
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Division of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Jannie
authors: J
authors: Borst
authors: Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium mmoser@ulb.ac.be.
authors: Muriel
authors: M
authors: Moser
mesh_terms: D000818:Animals; D053282:CD27 Ligand / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000378:metabolism
chemical_list: D053282:CD27 Ligand; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: costimulation; dendritic cells; inflammation; suppression; trogocytosis