IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-53593-8.html
   My bibliography  Save this article

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

Author

Listed:
  • Hongxing Shen

    (University of Alabama at Birmingham (UAB-SOM))

  • Oluwagbemiga A. Ojo

    (University of Alabama at Birmingham (UAB-SOM))

  • Haitao Ding

    (University of Alabama at Birmingham (UAB-SOM))

  • Logan J. Mullen

    (University of Alaska Fairbanks)

  • Chuan Xing

    (University of Alabama at Birmingham (UAB-SOM))

  • M. Iqbal Hossain

    (UAB-SOM)

  • Abdelrahman Yassin

    (University of Alabama at Birmingham (UAB-SOM))

  • Vivian Y. Shi

    (University of Alabama at Birmingham (UAB-SOM))

  • Zach Lewis

    (University of Alabama at Birmingham (UAB-SOM))

  • Ewa Podgorska

    (University of Alabama at Birmingham (UAB-SOM))

  • Shaida A. Andrabi

    (UAB-SOM)

  • Maciek R. Antoniewicz

    (University of Michigan)

  • James A. Bonner

    (University of Alabama at Birmingham (UAB-SOM)
    UAB-SOM)

  • Lewis Zhichang Shi

    (University of Alabama at Birmingham (UAB-SOM)
    UAB-SOM
    UAB-SOM
    UAB-SOM)

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.

Suggested Citation

  • 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. An, 2024. "HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53593-8
    DOI: 10.1038/s41467-024-53593-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-53593-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-53593-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Fotios Karagiannis & Konrad Peukert & Laura Surace & Marcel Michla & Fabian Nikolka & Mario Fox & Patricia Weiss & Caroline Feuerborn & Paul Maier & Susanne Schulz & Burcu Al & Benjamin Seeliger & Tob, 2022. "Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19," Nature, Nature, vol. 609(7928), pages 801-807, September.
    2. Erika L. Pearce & Matthew C. Walsh & Pedro J. Cejas & Gretchen M. Harms & Hao Shen & Li-San Wang & Russell G. Jones & Yongwon Choi, 2009. "Enhancing CD8 T-cell memory by modulating fatty acid metabolism," Nature, Nature, vol. 460(7251), pages 103-107, July.
    3. Patrick H. Maxwell & Michael S. Wiesener & Gin-Wen Chang & Steven C. Clifford & Emma C. Vaux & Matthew E. Cockman & Charles C. Wykoff & Christopher W. Pugh & Eamonn R. Maher & Peter J. Ratcliffe, 1999. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis," Nature, Nature, vol. 399(6733), pages 271-275, May.
    4. Sung Hoon Cho & Ariel L. Raybuck & Kristy Stengel & Mei Wei & Thomas C. Beck & Emmanuel Volanakis & James W. Thomas & Scott Hiebert & Volker H. Haase & Mark R. Boothby, 2016. "Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system," Nature, Nature, vol. 537(7619), pages 234-238, September.
    5. Hongxing Shen & Fengyuan Huang & Xiangmin Zhang & Oluwagbemiga A. Ojo & Yuebin Li & Hoa Quang Trummell & Joshua C. Anderson & John Fiveash & Markus Bredel & Eddy S. Yang & Christopher D. Willey & Zech, 2022. "Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Francisco R Fields & Niraja Suresh & Morgan Hiller & Stefan D Freed & Kasturi Haldar & Shaun W Lee, 2020. "Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-19, November.
    2. Marta Iborra-Pernichi & Jonathan Ruiz García & María Velasco de la Esperanza & Belén S. Estrada & Elena R. Bovolenta & Claudia Cifuentes & Cristina Prieto Carro & Tamara González Martínez & José Garcí, 2024. "Defective mitochondria remodelling in B cells leads to an aged immune response," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Yongkang Yang & Haiquan Lu & Chelsey Chen & Yajing Lyu & Robert N. Cole & Gregg L. Semenza, 2022. "HIF-1 Interacts with TRIM28 and DNA-PK to release paused RNA polymerase II and activate target gene transcription in response to hypoxia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Angela McNelly & Anne Langan & Danielle E. Bear & Alexandria Page & Tim Martin & Fatima Seidu & Filipa Santos & Kieron Rooney & Kaifeng Liang & Simon J. Heales & Tomas Baldwin & Isabelle Alldritt & Ha, 2023. "A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Zhihong Zhao & Guixiang Liao & Yongqiang Li & Shulu Zhou & Hequn Zou & Samitha Fernando, 2014. "Prognostic Value of Carbonic Anhydrase IX Immunohistochemical Expression in Renal Cell Carcinoma: A Meta-Analysis of the Literature," PLOS ONE, Public Library of Science, vol. 9(11), pages 1-16, November.
    6. Xing Liu & Jinhua Tang & Zixuan Wang & Chunchun Zhu & Hongyan Deng & Xueyi Sun & Guangqing Yu & Fangjing Rong & Xiaoyun Chen & Qian Liao & Shuke Jia & Wen Liu & Huangyuan Zha & Sijia Fan & Xiaolian Ca, 2024. "Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    7. Bonnie Huang & James D. Phelan & Silvia Preite & Julio Gomez-Rodriguez & Kristoffer H. Johansen & Hirofumi Shibata & Arthur L. Shaffer & Qin Xu & Brendan Jeffrey & Martha Kirby & Stacie Anderson & Yan, 2022. "In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Wenna Chi & Na Kang & Linlin Sheng & Sichen Liu & Lei Tao & Xizhi Cao & Ye Liu & Can Zhu & Yuming Zhang & Bolong Wu & Ruiqun Chen & Lili Cheng & Jing Wang & Xiaolin Sun & Xiaohui Liu & Haiteng Deng & , 2024. "MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Matteo Villa & David E. Sanin & Petya Apostolova & Mauro Corrado & Agnieszka M. Kabat & Carmine Cristinzio & Annamaria Regina & Gustavo E. Carrizo & Nisha Rana & Michal A. Stanczak & Francesc Baixauli, 2024. "Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    10. Sophie Hillion & Anjelica Miranda & Christelle Dantec & Marina Boudigou & Laëtitia Pottier & Divi Cornec & Raul M. Torres & Roberta Pelanda, 2024. "Maf expression in B cells restricts reactive plasmablast and germinal center B cell expansion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Jianping Wang & Bin Zhao & Jingmin Che & Peng Shang, 2023. "Hypoxia Pathway in Osteoporosis: Laboratory Data for Clinical Prospects," IJERPH, MDPI, vol. 20(4), pages 1-22, February.
    12. Qingdong Ke & Thomas Kluz & Max Costa, 2005. "Down-Regulation of the Expression of the FIH-1 and ARD-1 Genes at the Transcriptional Level by Nickel and Cobalt in the Human Lung Adenocarcinoma A549 Cell Line," IJERPH, MDPI, vol. 2(1), pages 1-4, April.
    13. Rens Peeters & Jorge Cuenca-Escalona & Esther A. Zaal & Anna T. Hoekstra & Anouk C. G. Balvert & Marcos Vidal-Manrique & Niek Blomberg & Sjoerd J. Deventer & Rinke Stienstra & Julia Jellusova & Martin, 2022. "Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    14. Meng-Han Wu & Felipe Valenca-Pereira & Francesca Cendali & Emily L. Giddings & Catherine Pham-Danis & Michael C. Yarnell & Amanda J. Novak & Tonya M. Brunetti & Scott B. Thompson & Jorge Henao-Mejia &, 2024. "Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    15. Justin A. Guerrero & Dorota D. Klysz & Yiyun Chen & Meena Malipatlolla & Jameel Lone & Carley Fowler & Lucille Stuani & Audre May & Malek Bashti & Peng Xu & Jing Huang & Basil Michael & Kévin Contrepo, 2024. "GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53593-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.