Non-redundant activity of GSK-3α and GSK-3β in T cell-mediated tumor rejection
| Autor: | Aarren J. Mannion, Alison Taylor, Gary Shaw, Christopher E. Rudd, Kenneth A. MacLennan, Graham P. Cook, Lynette Steele |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene isoform Science medicine.medical_treatment T cell macromolecular substances 02 engineering and technology Article immunology 03 medical and health sciences cell biology medicine cancer Cytotoxic T cell functional aspects of cell biology Glycogen synthase Multidisciplinary biology Chemistry Gene targeting Immunotherapy 021001 nanoscience & nanotechnology Cell biology Granzyme B 030104 developmental biology medicine.anatomical_structure biology.protein 0210 nano-technology CD8 |
| Zdroj: | iScience, Vol 24, Iss 6, Pp 102555-(2021) iScience |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical abstract Highlights • Conditional knockouts reveal a non-redundant role for GSK-3α and GSK-3β in T cells. • GSK-3α and GSK-3β act together to enhance PD-1 expression. • GSK-3β depletion alone enhances T cell mediated tumor rejection. • GSK-3β plays an important role in regulating T cell-mediated anti-tumor immunity. Cancer; Cell biology; Functional aspects of cell biology; Immunology |
| Databáze: | OpenAIRE |
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