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- Title
PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity.
- Authors
Helou, Doumet Georges; Shafiei-Jahani, Pedram; Lo, Richard; Howard, Emily; Hurrell, Benjamin P.; Galle-Treger, Lauriane; Painter, Jacob D.; Lewis, Gavin; Soroosh, Pejman; Sharpe, Arlene H.; Akbari, Omid
- 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. PD-1 is a checkpoint inhibitory immune receptor that restrains proliferation and effector functions of a variety of cells, including ILC2s. Here the authors present a human PD-1 agonist that limits ILC2-dependent allergic airway disease in humanized mice and provide evidence that PD-1 signaling alters ILC2 function by modulation of cell metabolism.
- Subjects
INNATE lymphoid cells; CELL metabolism; PNEUMONIA; CELL proliferation; METABOLISM
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-17813-1