Journal Article

Dichotomous metabolic networks govern human ILC2 proliferation and function

Di Santo, James P., Surace, Laura, Doisne, Jean-Marc, Petrosemoli, Natalia, Croft, Carys A., Dardalhon, Valerie, Buchrieser, Carmen, Thaller, Anna, Cama, Antonia, Musumeci, Olimpia, Marie, Solenne, Amit, Ido, Escoll, Pedro, Guillemot, Vincent, Taylor, Naomi, Topazio, Davide

2021

Overview

Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (T H 2) 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 ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (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 ILC2s, offering new strategies to target ILC2s in disease settings. ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2504/2506 / 631/45/127/1213 / Amino acids / Amino Acids, Branched-Chain / Amino Acids, Branched-Chain - metabolism / Arginine / Arginine - metabolism / Biomedical and Life Sciences / Biomedicine / Case-Control Studies / Cell metabolism / Cell Proliferation / Cell Proliferation - drug effects / Cells, Cultured / Cytokines / Cytokines - metabolism / Energy Metabolism / Energy Metabolism - drug effects / Glycolysis / Health aspects / Homeostasis / Humans / Immune response / Immune system / Immunity, Innate / Immunity, Innate - drug effects / Immunological research / Immunology / Infectious Diseases / Interleukin 13 / Interleukin-33 / Interleukin-33 - pharmacology / Letter / Life Sciences / Lymphocyte Activation / Lymphocyte Activation - drug effects / Lymphocytes / Lymphocytes T / Lymphoid cells / Metabolic networks / Metabolic pathways / Metabolism / Metabolomics / Mitochondria / Mitochondria - metabolism / Mitochondrial Diseases / Mitochondrial Diseases - diagnosis / Mitochondrial Diseases - immunology / Mitochondrial Diseases - metabolism / Natural killer cells / Oxidative phosphorylation / Phenotype / Phosphorylation / Physiological aspects / Rapamycin / Th2 Cells / Th2 Cells - drug effects / Th2 Cells - immunology / Th2 Cells - metabolism / TOR protein