Dichotomous metabolic networks govern human ILC2 proliferation and function

Group 2 innate lymphoid cells (ILC2) represent innate homologues of Th2 cells that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited and its key regulators are unknown. Here we show that circulating “naïve” ILC2 have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than NK cells. Accordingly, ILC2 are severely reduced in patients with mitochondrial disease and impaired OXPHOS. Metabolomic and nutrient receptors analysis reveals ILC2 uptake amino acids to sustain OXPHOS at steady-state. Upon activation with interleukin 33 (IL-33), ILC2 become highly proliferative relying on glycolysis and mTOR to produce IL-13, while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2, offering new strategies to target ILC2 in disease settings. CRTh2+ ILC2 and CD56Dim NK cells were freshly isolated by FACS from peripheral blood of three healthy adult individuals. In total, 6 samples were analyzed and comparing between two cell populations.