Notch signaling promotes the plasticity of group-2 innate lymphoid cells

Mechanisms underlying lymphocyte lineage stability and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, “plastic” inflammatory ILC2 (iILC2) can co-produce both type-2 cytokines and also the ILC3-characteristic cytokine IL-17. Mechanisms that elicit this lineage plasticity, and the importance in health and disease, remain unclear. Here we show that iILC2 are potent inducers of airway inflammation in response to acute house dust mite challenge. We find that Notch signaling induces lineage plasticity of mature ILC2 and drives the conversion of nILC2 into iILC2. Acute blockade of Notch signaling abolished functional iILC2, but not nILC2, in vivo. Exposure of isolated nILC2 to Notch ligands induced Rorc expression and elicited dual IL-13/IL-17 production, converting nILC2 into iILC2. Together these results reveal a novel role for Notch signaling in eliciting ILC2 plasticity and driving the emergence of highly pro-inflammatory innate lymphocytes.