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Comment on: Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation

Cellular & Molecular Immunology volume 22, pages 557–558 (2025)Cite this article

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A Comment to this article was published on 02 April 2025

The Original Article was published on 09 August 2023

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We would like to discuss the findings of Fu et al. (2023), published in the Nature journal CMI, regarding the role of GSK-3 in T-cell biology [1]. While their findings offer valuable perspectives, on the basis of prior studies and our analysis, we propose several complementary explanations that may help reconcile their recent results with existing knowledge in the field. Their study revealed that genetic deletion of GSK3α/β in activated CD8+ T cells led to increased T-cell exhaustion and reduced antitumor responses. In contrast, multiple laboratories have demonstrated enhanced tumor rejection and improved chronic viral responses with GSK-3 inhibition. Taylor et al. first demonstrated that GSK-3 inactivation or siRNA downregulation led to reduced PD-1 and LAG3 levels, resulting in improved viral and tumor clearance [2,3,4]. This finding was confirmed by the Huntington group via the use of a novel small inhibitory molecule (SMI) [5]. Similarly, the Goronzy laboratory reported that GSK3β inhibition restored the activation and cytokine production of aged T cells [6], whereas the Sampath laboratory reported that GSK-3 inhibition improved CAR-T-cell function while reducing PD-1 levels [7]. These findings are underscored by the promising results of the use of GSK-3 inhibitors such as elraglusib (9-ING-41) in prostate cancer treatment [5].

We suggest examining several methodological nuances that may help clarify the observed outcomes. One key area that warrants careful consideration is the nature of the knockout (KO) targeting of cells. This technique could provide valuable insights into the underlying mechanisms and help bridge different observations in the field. While Fu et al. [1] employed granzyme B (GZMB)-Cre for GSK-3 deletion and suggested that the KO was specific for CD8+ T cells, GZMB expression extends well beyond this population. In fact, the GZMB-Cre system also targets NK cells and cytolytic CD4+ T cells, regulatory suppressor CD4+ T cells (Tregs), Group 1 ILCs, mast cells, and macrophages. This phenomenon is particularly relevant for Tregs, where in certain instances, granzyme B has been reported to be integral to their suppressive function [8]. The effect of deleting GSK-3 with the GZMB-Cre model would have affected a broad range of immune cells beyond CD8+ T-cells with the capacity to interact with each other.

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References

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Authors and Affiliations

  1. Department of Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada

    Bastien Moës & Christopher E. Rudd

  2. Department of Microbiology, Infection and Immunology, Université de Montréal, Montreal, QC, Canada

    Bastien Moës & Christopher E. Rudd

  3. Cell Signaling and Immunotherapy Section, Centre de Recherche Hôpital Maisonneuve-Rosemont (CR-HMR), Montreal, QC, H1T 2M4, Canada

    Bastien Moës & Christopher E. Rudd

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  1. Bastien Moës
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Correspondence to Christopher E. Rudd.

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Moës, B., Rudd, C.E. Comment on: Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation. Cell Mol Immunol 22, 557–558 (2025). https://doi.org/10.1038/s41423-025-01277-8

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