Metabolic Vulnerabilities of ILC2 and Th2 Cells Reveal Novel Targets in Allergic Asthma

A team of researchers from the University Hospital Bonn and the University of Bonn discovered that certain immune cells in patients with allergic asthma—type 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells—only survive because they activate a special antioxidant protection mechanism. The investigators wrote that their findings suggest metabolic vulnerability that can be utilized to develop other therapeutic approaches in asthma treatment.¹

In allergic asthma, ILC2 and Th2 cells are key drivers of inflammation. They produce messenger substances that increase mucus formation and the influx of immune cells. Simultaneously, the inflamed lung tissue is rich in free fatty acids and oxidative molecules, conditions that typically endanger cells. Asthma driven by dysregulated type 2 immunity is characterized by the production of the cytokines IL-4, IL-5, IL-9, and IL-13 from ILC2 and CD4+ Th2 cells. Among these, IL-13 acts directly on airway epithelial cells to increase mucus production, whereas IL-5 promotes the recruitment of eosinophils into the airways.¹

In this study, the research team evaluated the activity of cells, inflammation, and characteristics of disease in mouse models with allergic asthma by examining the metabolic constraints that facilitate ILC2 expansion within lung tissue. Their findings indicated that the activation in the context of allergic airway inflammation promotes metabolic flexibility driven by coordinated lipid and metabolism. Although lipids are a major nutrient source for ILC2, their use depends on the availability of cystine to balance cellular reactive oxygen species and lipid peroxidation and to protect against ferroptosis. In human patients, a higher amount of cysteine is associated with a higher probability of asthma, meaning that cystine availability is linked to chronic airway inflammation.¹

“These immune cells operate in an environment that is actually toxic to them. They only survive because they ramp up their own protective programs to an extreme degree,” first author Chantal Wientjens, Institute of Chemistry and Clinical Pharmacology, University Hospital Bonn, and doctoral student at the University of Bonn, said in a news release. “Our data show that as soon as we specifically disrupt this protection, the cells lose their ability to drive allergic inflammation.”²

Further, the activation of ILC2s is strongly related to increased expression of proferroptotic pathways linked to anabolic lipid metabolism and the procurement and integration of external polyunsaturated fatty acids into cellular membranes. This metabolic feature is dependent on the simultaneous suppression of cellular ROS and lipid peroxidation through upregulation of the antiferroptotic and antioxidant systems glutathione peroxidase 4 (GPX4) and thioredoxin (TXN). Therefore, ablation of GPX4 and TXN reductase 1 (TXNRD1) in pathogenic ILC2s or the inhibition of TXNRD1 results in impaired lipid metabolism and hinders the accumulation of ILC2s that reside in the airways. The authors also suggested their data suggest the expression of GPX4 and acquisition of cystine in allergen-activated ILC2s may also be important to balance increased iron uptake.¹

“Pathogenic type 2 immune cells are surprisingly dependent on their antioxidant ‘lifeline’. This opens up a new therapeutic venue: In the future, we could slow down the metabolism of overactive immune cells without weakening the immune system as a whole. This is an exciting prospect, even though we are still in the early stages of research,” study leader Christoph Wilhelm, chair of immunopathology at the Institute for Clinical Chemistry and Clinical Pharmacology at University Hospital Bonn, member of the ImmunoSensation Cluster of Excellence at the University of Bonn, concluded.²

REFERENCES

1. Wientjens C, Doverman M, Zurkovic J, et al. Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation. Immunity. 2025. doi:10.1016/j.immuni.2025.11.018

2. Universitatsklinikum Bonn. New vulnerability of asthma immune cells discovered. News release. December 11, 2025. Accessed December 19, 2025. https://www.eurekalert.org/news-releases/1109510