PGE2 Enhances Human ILC3 Function but Constrains ILC2‐to‐ILC3 Plasticity

Type 2 innate lymphoid cells (ILC2) drive eosinophilic asthma, whereas ILC3 and plastic ILC2/3 states are implicated in neutrophilic and mixed granulocytic disease endotypes. While lipid mediators regulate ILC2 function and airway inflammation, their role in human ILC3 biology and ILC plasticity remains poorly defined. We investigated how eicosanoid biosynthesis and signalling regulate human ILC2 and ILC3 function across canonical and plastic states. Here, we identified distinct prostaglandin (PG) profiles across ILC subsets. Unlike ILC2, which produce and rely on PGD 2 , ILC3 produced PGE 2 , which stimulated their release of IL‐17F and IL‐22. ILC2‐to‐ILC3 plasticity induced a biosynthetic switch towards PGE 2 production that correlated with IL‐17A and IL‐17F expression. However, subset‐intrinsic prostaglandin responses were preserved: hybrid ILC2/3 phenotypes, unlike bona fide ILC3, remained susceptible to PGE 2 ‐mediated inhibition, indicating a key functional distinction between these populations.Collectively, our data identify PGE 2 as a central regulator of ILC3 function, paralleling the role of PGD 2 in ILC2. These findings position PGs as key orchestrators of ILC subset function and plasticity and provide mechanistic insights into the regulation of ILC3 and hybrid ILC2/3 phenotypes associated with neutrophilic and mixed granulocytic asthma.