Nature Communications (Oct 2024)

HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells

  • Hongxing Shen,
  • Oluwagbemiga A. Ojo,
  • Haitao Ding,
  • Logan J. Mullen,
  • Chuan Xing,
  • M. Iqbal Hossain,
  • Abdelrahman Yassin,
  • Vivian Y. Shi,
  • Zach Lewis,
  • Ewa Podgorska,
  • Shaida A. Andrabi,
  • Maciek R. Antoniewicz,
  • James A. Bonner,
  • Lewis Zhichang Shi

DOI
https://doi.org/10.1038/s41467-024-53593-8
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 17

Abstract

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Abstract Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α –/–) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl –/–) increases IFN-γ production. Hypoxic Hif1α –/– T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α –/– mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α –/– T cells and re-sensitizing Hif1α –/– tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.