Mark Rusznak, Shinji Toki, Yajing B. Hao, Marc J. C. Todd, Liddy Malone, Julia F. Goodhead, Catherine Dupuy, Weisong Zhou, Dominique Babin, Christian M. Warren, Masako Abney, Matthew T. Stier, Christopher M. Thomas, Jing Li, Justin Jacobse, Andrew P Pahnke, Mark I. Petrovic, Jacqueline-Yvonne Cephus, Shelby N Kuehnle, M. Wade Calcutt, Allison E. Norlander, Yan Fang, Jeremy A. Goettel, Darla R. Miller, Rachel Lynch, Daniel P. Cook, Dawn C. Newcomb, Fei Zou, R. Stokes Peebles
Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.