Abstract
SummaryGlycogen 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.
Highlights
Glycogen synthase kinase-3 (GSK-3) was first discovered in 1980 as a regulatory kinase which phosphorylates and inhibits glycogen synthase (Embi et al, 1980) and has since been implicated in several disease states and key cellular processes, including Wnt, insulin, and Hedgehog signaling (Matthews and Cantrell, 2009)
GSK-3 has two co-expressed isoforms, GSK-3a and GSK-3b. We demonstrate that both isoforms contribute to T cell function to different degrees
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
Summary
Glycogen synthase kinase-3 (GSK-3) was first discovered in 1980 as a regulatory kinase which phosphorylates and inhibits glycogen synthase (Embi et al, 1980) and has since been implicated in several disease states and key cellular processes, including Wnt, insulin, and Hedgehog signaling (Matthews and Cantrell, 2009). Two isoforms of GSK-3 have been reported in mammals; a 51 kDa GSK-3a and a 47 kDa GSK-3b isoform, encoded by the unlinked Gsk3a and Gsk3b genes, respectively These two isoforms exhibit 98% homology in their kinase domains but only 36% identity in the last 76 C-terminal amino acid residues. An unusual aspect of GSK-3 is that it is constitutively active in resting cells (Embi et al, 1980; Woodgett, 1990) and its inactivation occurs through phosphorylation of specific serine residues (Ser in GSK-3b, Ser in GSK-3a) (Hughes et al, 1993; Rayasam et al, 2009). Glycogen synthase is primed by casein kinase 2 (CK2) prior to its subsequent phosphorylation and inactivation by GSK-3 (Picton et al, 1982)
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