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

Doumet Georges Helou,Emily Howard,Jacob D Painter,Arlene H Sharpe,Pejman Soroosh,Benjamin P Hurrell,Lauriane Galle-Treger,Gavin Lewis,Omid Akbari,Pedram Shafiei-Jahani,Richard Lo

doi:10.1038/s41467-020-17813-1

Doumet Georges Helou, Emily Howard + Show 9 more

Open Access

https://doi.org/10.1038/s41467-020-17813-1

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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.

Highlights

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR)
Our results revealed that the lack of PD-1 increased the relative levels of several intermediates and end metabolites involved in glutamine metabolism such as glutamic acid, N-methyl glutamate, N-acetyl glutamic acid (NAG), and ornithine (Fig. 4h–k)
We have demonstrated that PD-1 regulates ILC2s to ameliorate AHR and control lung inflammation

Summary

Introduction

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. As the blockade of PD-1 exacerbates AHR, we 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. Animal models are useful and can closely mimic clinical features of asthma, mainly airway hyperreactivity (AHR), which relies on T-helper 2 (Th2) cytokine secretion; interleukin (IL)-5 promotes eosinophil recruitment to the lungs, while IL-13 induces goblet cell hyperplasia and mucus production[3]. Our findings provide new insights into the mechanisms of ILC2 regulation, which might be used to develop new approaches for the treatment of allergic asthma

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