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

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 and Omid Akbari ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17813-1

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