Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3{beta} inhibition.
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.
Graham
Jay A
JA
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Fray
Michael
M
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
de Haseth
Stephanie
S
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Lee
Kang Mi
KM
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Lian
Moh-Moh
MM
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Chase
Catharine M
CM
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Madsen
Joren C
JC
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.
Markmann
James
J
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Benichou
Gilles
G
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Colvin
Robert B
RB
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Cosimi
A Benedict
AB
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Deng
Shaoping
S
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Kim
James
J
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114.
Alessandrini
Alessandro
A
From the Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02114. Electronic address: aalessandrini@partners.org.
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
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