Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity.

A unique subpopulation of memory T helper 2 (TH2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2hi memory TH2 cells remain unclear. We show using a mouse model of chronic allergic airway inflammation that long-chain unsaturated fatty acids (LC-UFAs) accumulate in the inflammatory milieu during chronic airway inflammation. Activated TH2 cells take up LC-UFAs, transiently store them in lipid droplets (LDs), and catabolize LDs through lipolysis and microlipophagy. LD catabolism regulated by adipose triglyceride lipase (ATGL) activates peroxisome proliferator-activated receptor γ (PPARγ). PPARγ then binds the Il1rl1 locus encoding ST2 and induces ST2hi effector and memory TH2 cells. In eosinophilic chronic rhinosinusitis, CD45RO+ CD4 T cells in nasal polyps exhibit microlipophagy and an accessible IL1RL1 enhancer, indicating that these mechanisms are conserved in humans. Thus, the storage and catabolism of inflammatory milieu-derived LC-UFAs direct pathogenic adaptive type 2 immunity, offering potential therapeutic strategies for persistent allergic inflammation.