ILC3s integrate glycolysis and mitochondrial production of reactive oxygen species to fulfill activation demands

Blanda Di Luccia, Susan Gilfillan, Marina Cella, Marco Colonna, Stanley Ching Cheng Huang

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter rodentium infection. mTORC1 induces activation of HIF1α, which reprograms ILC3 metabolism toward glycolysis and sustained expression of RORγt. However, in contrast to Th17, ILC3 activation requires mROS production; rather than inducing an alternative regulatory fate as it does in CD4 T cells, mROS stabilizes HIF1α and RORγt in ILC3s and thereby promotes their activation. We conclude that ILC3 activation relies on a metabolic program that integrates glycolysis with mROS production.

Original languageEnglish
Pages (from-to)2231-2241
Number of pages11
JournalJournal of Experimental Medicine
Volume216
Issue number10
DOIs
StatePublished - 2019

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