Autophagy is critical for group 2 innate lymphoid cell metabolic homeostasis and effector function

Abstract Background Allergic asthma is a chronic inflammatory disorder that is characterized with airway hyperreactivity (AHR) and driven by Th2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amount of Th2 cytokines and contribute to the development of AHR. Autophagy is a cellular degradation pathway that recycles cytoplasmic content. However, the role of autophagy in ILC2s remains to be fully elucidated. Objective We characterized the effects of autophagy deficiency on ILC2 effector functions and metabolic balance. Methods ILC2s from autophagy deficient mice were isolated to evaluate proliferation, apoptosis, cytokine secretion, gene expression and cell metabolism. Also, autophagy deficient ILC2s were adoptively transferred into Rag-/-GC-/- mice, which were them challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation. Results We demonstrate that autophagy is extensively used by activated ILC2s to maintain their homeostasis and effector functions. Deletion of the critical autophagy gene Atg5 resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to utilize fatty acid oxidation and strikingly promoted glycolysis as evidenced by our transcriptomic and metabolite analyses. This shift of fuel dependency led to impaired homeostasis and Th2 cytokine production, thus inhibiting the development of ILC2-mediated AHR. Notably, this metabolic reprogramming was also associated with an accumulation of dysfunctional mitochondria producing excessive reactive oxygen species. Conclusion These findings provide new insights into the metabolic profile of ILC2s and suggest that modulation of fuel dependency by autophagy is a potentially new therapeutic approach to target ILC2 dependent inflammation.