Non-redundant activity of GSK-3α and GSK-3β in T cell-mediated tumor rejection
Lynette Steele,
Aarren J. Mannion,
Gary Shaw,
Kenneth A. Maclennan,
Graham P. Cook,
Christopher E. Rudd,
Alison Taylor
Affiliations
Lynette Steele
Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK
Aarren J. Mannion
Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK; Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
Gary Shaw
Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK
Kenneth A. Maclennan
Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK
Graham P. Cook
Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK
Christopher E. Rudd
Division of Immunology-Oncology Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; Division of Experimental Medicine, Department of Medicine, McGill University Health Center, McGill University, Montreal, Quebec H4A 3J1, Canada
Alison Taylor
Leeds Institute of Medical Research, University of Leeds, School of Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK; Corresponding author
Summary: Glycogen synthase kinase-3 (GSK-3) is a positive regulator of PD-1 expression in CD8+ T cells and GSK-3 inhibition enhances T cell function and is effective in the control of tumor growth. GSK-3 has two co-expressed isoforms, GSK-3α and GSK-3β. Using conditional gene targeting, we demonstrate that both isoforms contribute to T cell function to different degrees. Gsk3b−/− mice suppressed tumor growth to the same degree as Gsk3a/b−/− mice, whereas Gsk3a−/− mice behaved similarly to wild-type, revealing an important role for GSK-3β in regulating T cell-mediated anti-tumor immunity. The individual GSK-3α and β isoforms have differential effects on PD-1, IFNγ, and granzyme B expression and operate in synergy to control PD-1 expression and the infiltration of tumors with CD4 and CD8 T cells. Our data reveal a complex interplay of the GSK-3 isoforms in the control of tumor immunity and highlight non-redundant activity of GSK-3 isoforms in T cells, with implications for immunotherapy.
