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PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity

Author

Listed:
  • Doumet Georges Helou

    (University of Southern California)

  • Pedram Shafiei-Jahani

    (University of Southern California)

  • Richard Lo

    (University of Southern California)

  • Emily Howard

    (University of Southern California)

  • Benjamin P. Hurrell

    (University of Southern California)

  • Lauriane Galle-Treger

    (University of Southern California)

  • Jacob D. Painter

    (University of Southern California)

  • Gavin Lewis

    (Janssen Research and Development)

  • Pejman Soroosh

    (Janssen Research and Development)

  • Arlene H. Sharpe

    (Harvard Medical School)

  • Omid Akbari

    (University of Southern California)

Abstract

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.

Suggested Citation

  • Doumet Georges Helou & Pedram Shafiei-Jahani & Richard Lo & Emily Howard & Benjamin P. Hurrell & Lauriane Galle-Treger & Jacob D. Painter & Gavin Lewis & Pejman Soroosh & Arlene H. Sharpe & Omid Akbar, 2020. "PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17813-1
    DOI: 10.1038/s41467-020-17813-1
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    Cited by:

    1. Lauriane Galle-Treger & Doumet Georges Helou & Christine Quach & Emily Howard & Benjamin P. Hurrell & German R. Aleman Muench & Pedram Shafiei-Jahani & Jacob D. Painter & Andrea Iorga & Lily Dara & Ju, 2022. "Autophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Thomas Hollin & Steven Abel & Alejandra Falla & Charisse Flerida A. Pasaje & Anil Bhatia & Manhoi Hur & Jay S. Kirkwood & Anita Saraf & Jacques Prudhomme & Amancio De Souza & Laurence Florens & Jacqui, 2022. "Functional genomics of RAP proteins and their role in mitoribosome regulation in Plasmodium falciparum," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Emily Howard & Benjamin P. Hurrell & Doumet Georges Helou & Pedram Shafiei-Jahani & Spyridon Hasiakos & Jacob Painter & Sonal Srikanth & Yousang Gwack & Omid Akbari, 2023. "Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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