PD-1 agonist modulates ILC2 metabolism and ameliorates airway hyperreactivity

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.109-109.15
• Main Authors: Helou, Georges Doumet, Shafiei-Jahani, Pedram, Lo, Richard, Howard, Emily Diane, Hurrell, Benjamin P, Galle-Treger, Lauriane, Painter, Jacob Dean, Lewis, Gavin, Soroosh, Pejman, Sharpe, Arlene H, Akbari, Omid
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.109.15

Allergic asthma is a chronic inflammatory disease characterized by airway hyperreactivity (AHR) and type-2 immune response. Type-2 innate lymphoid cells (ILC2s) mimic T helper 2 (Th2) cells in cytokine secretion and are among the first pulmonary immune responders to the allergen-induced alarmins. Programmed cell death protein-1 (PD-1) is known as an immune checkpoint equipped with tyrosine-based inhibitory motifs in the cytoplasmic tail. Since PD-1 is associated with immune regulation in many inflammatory diseases, the objective of this study was to investigate the role of PD-1 in the initiation and development of AHR. Lung function tests, RNA sequencing, flow cytometry, targeted metabolomic assays, and adoptive transfer experiments were principally used to explore the role of PD-1 in AHR mouse models and in human ILC2s. Using IL-33 and Alternaria alternata models, we have demonstrated that PD-1 knockout mice develop a higher AHR and lung inflammation as compared to control wild-type mice. In particular, PD-1 is highly inducible on lung ILC2s and downregulates their effector functions. Moreover, PD-1 controls glycolysis and methionine catabolism, limiting, therefore, the proliferation of activated pulmonary ILC2s. In line with mice data, PD-1 is inducible and functional in human ILC2s in response to IL-33. To confirm the translational relevance of our findings, we tested a novel human PD-1 agonist in vitro and in a humanized mouse model of AHR. Interestingly, the PD-1 agonist decreases human ILC2 activation and is able to dampen AHR and lung inflammation. Altogether this study reveals the protective role of PD-1 as regulators of ILC2s and highlights for the first time the therapeutic potential of PD-1 agonists in allergic asthma. Supported by grants from NIH: R01 ES025786, R01 ES021801, R01 HL144790, and R21 AI109059 (O.A.)