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Tetramerization of pyruvate kinase M2 attenuates graft-versus-host disease by inhibition of Th1 and Th17 differentiation

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Abstract

Lethal graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem-cell transplantation (Allo-HSCT). Pyruvate kinase M2 (PKM2) is essential for CD4+ T-cell differentiation. Using the well-characterized mouse models of Allo-HSCT, we explored the effects of TEPP-46-induced PKM2 tetramerization on GVHD and graft-versus-leukemia (GVL) activity. TEPP-46 administration significantly improved the survival rate of GVHD. The severity of GVHD and histopathological damage of GVHD-targeted organs were obviously alleviated by PKM2 tetramerization. Additionally, tetramerized PKM2 inhibited the activation of NF-κB pathway and decreased the inflammation level of GVHD mice. PKM2 tetramerization blocked Th1 and Th17 cell differentiation and secretion of pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-17). Meanwhile, differentiation of Treg cells and IL-10 secretion were promoted by tetramerized PKM2. These findings demonstrated that PKM2 enhanced the augment of Th1 and Th17 cells to accelerate the progression of GVHD, and allosteric activation of PKM2 targeted Th1 and Th17 cells attenuated GVHD. Furthermore, we also confirmed that TEPP-46 administration did not compromise GVL activity and resulted in slightly improvement of leukemia-free survive. Thus, targeting Th1 and Th17 cell response with PKM2 allosteric activator may be a promising therapeutic strategy for GVHD prevention while preserving the GVL activity in patients receiving Allo-HSCT.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was funded by the Project of Tackling of Key Scientific and Technical Problems in Henan Province (No. 222102310172).

Funding

This research was funded by the Project of Tackling of Key Scientific and Technical Problems in Henan Province (No. 222102310172).

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Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, 1#, East Jianshe Road, Erqi District, Zhengzhou, Henan, China

    Meng Wang, Qiu-Jie Li & Jing-Lan Zhang

  2. Surgical Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Hua-Yan Zhao

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Contributions

MW: conceptualization, project administration, and writing—original draft. Q-JL: data curation, formal analysis, and writing—original draft. H-YZ: investigation, data curation, and writing—review and editing. J-LZ: data curation and visualization.

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Correspondence to Meng Wang.

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This study was performed in line with the principles of the Guide for the Care and Use of Laboratory Animals. Approval was granted by Ethical Review Committee of Life Sciences, Zhengzhou University.

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Wang, M., Li, QJ., Zhao, HY. et al. Tetramerization of pyruvate kinase M2 attenuates graft-versus-host disease by inhibition of Th1 and Th17 differentiation. Human Cell 37, 633–647 (2024). https://doi.org/10.1007/s13577-024-01033-6

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