Bcl2 supports survival and metabolic fitness of quiescent tissue-resident ILC3

King, J. I.; Melo-Gonzalez, F.; Malengier-Devlies, B.; Tacho-Pinot, R.; Magalhaes, M. S.; Hodge, S. H.; Romero Ros, X.; Gentek, R.; Hepworth, M. R.

doi:10.1101/2023.02.27.528945

bioRxiv · 10.1101/2023.02.27.528945

Bcl2 supports survival and metabolic fitness of quiescent tissue-resident ILC3

King, J. I.·Melo-Gonzalez, F.·Malengier-Devlies, B.·Tacho-Pinot, R.·Magalhaes, M. S.·Hodge, S. H.·Romero Ros, X.·Gentek, R.·Hepworth, M. R.

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Abstract

Group 3 innate lymphoid cells (ILC3) are potent effector cells with critical roles in enforcing immunity, barrier integrity and tissue homeostasis along the gastrointestinal tract. ILC3 are considered to be primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages. However, the mechanisms through which ILC3 are maintained within these tissues are poorly understood. Here, we report that ILC3 are minimally replenished from bone marrow precursors in healthy adult mice, persist in the tissue for extended periods of time in the gut, and display a quiescent phenotype. Strikingly, despite robustly producing cytokines, LTi-like ILC3 remain non-proliferative during enteric bacterial infection. Survival of LTi-like ILC3 was found to be dependent upon the balance of the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein Bcl-2 was required for the survival of LTi-like ILC3 but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a quiescent-like population that persists independently of haematopoietic replenishment to survive within the tissue microenvironment.

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King, J. I., Melo-Gonzalez, F., Malengier-Devlies, B., Tacho-Pinot, R., Magalhaes, M. S., Hodge, S. H., Romero Ros, X., Gentek, R., Hepworth, M. R.. 2023-02-28. Bcl2 supports survival and metabolic fitness of quiescent tissue-resident ILC3. https://doi.org/10.1101/2023.02.27.528945

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