title: Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3{beta} inhibition.
abstract: The mechanism by which regulatory T (Treg) cells suppress the immune response is not well defined. A recent study has shown that β-catenin prolongs Treg cell survival. Because β-catenin is regulated by glycogen synthase kinase 3β (GSK-3β)-directed phosphorylation, we focused on GSK-3β and the role it plays in Treg cell function. Inhibition of GSK-3β led to increased suppression activity by Treg cells. Inhibitor-treated Treg cells exhibited prolonged FoxP3 expression and increased levels of β-catenin and of the antiapoptotic protein Bcl-xL. Systemic administration of GSK-3β inhibitor resulted in prolonged islet survival in an allotransplant mouse model. Our data suggest that GSK-3β could be a useful target in developing strategies designed to increase the stability and function of Treg cells for inducing allotransplant tolerance or treating autoimmune conditions.
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Jay A
authors: JA
authors: Graham
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Michael
authors: M
authors: Fray
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Stephanie
authors: S
authors: de Haseth
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Kang Mi
authors: KM
authors: Lee
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Moh-Moh
authors: MM
authors: Lian
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Catharine M
authors: CM
authors: Chase
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114; Division of Cardiac Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors: Joren C
authors: JC
authors: Madsen
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: James
authors: J
authors: Markmann
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Gilles
authors: G
authors: Benichou
authors: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors: Robert B
authors: RB
authors: Colvin
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: A Benedict
authors: AB
authors: Cosimi
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: Shaoping
authors: S
authors: Deng
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
authors: James
authors: J
authors: Kim
authors: From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114. Electronic address: aalessandrini@partners.org.
authors: Alessandro
authors: A
authors: Alessandrini
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology; D014184:Transplantation, Homologous; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051020:bcl-X Protein; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3