Maintenance and Metabolism of Intestinal ILC3

Abstract

Innate lymphoid cells (ILC) are rare effector lymphocytes that are relatively enriched at barrier tissues with critical roles in promoting immunity and tissue homeostasis. Group 3 ILC (ILC3) are particularly abundant along the gastrointestinal tract (GI tract) where they enforce intestinal immunity during embryogenesis and adulthood. ILC3 have the capacity to be protective and promote gut homeostasis, however other studies have highlighted an inflammatory potential of ILC3 in disease as well. These contradictory findings in the field may be explained in part by ILC3 heterogeneity - with 3 main ILC3 subsets identified – double negative (DN) ILC3, natural cytotoxicity receptor-expressing (NCR+) ILC3 and lymphoid tissue inducer-like (LTi-like) ILC3. These three ILC3 subsets exhibit clear differences in ontogeny, transcriptional activity, effector functions and tissue localisation, and have been shown to evoke different roles in both protection and inflammation in the GI tract. Emerging evidence suggests ILC3 subsets are strictly tissue-resident cells but the mechanisms that maintain ILC3 within the intestines remains poorly understood. Here we show that ILC3 are not readily replaced by newly generated ILC3 from the bone marrow and are instead maintained long-term independently of peripheral replenishment. We observe proliferative capacity from DN ILC3 and NCR+ ILC3 that may support their means of maintenance through self-renewal. Strikingly, LTi-like ILC3 exhibited no sign of proliferative capacity even when responding to infection. Intriguingly, the quiescent-like LTi-like ILC3 highly expressed pro-survival protein Bcl-2 that was required for their survival. Furthermore, LTi-like ILC3 utilise oxidative phosphorylation (OXPHOS) to provide energy to facilitate their capacity to produce IL-22, but at the cost of generating metabolic stress. Notably, Bcl-2 facilitates LTi-like ILC3 survival by protecting against OXPHOS-mediated stress and highlights a novel mechanism by which LTi-like ILC3 can readily execute effector functions in the absence of proliferation. These findings further define the contrasting biology between ILC3 subsets that underpins their immune functions and could explain the differing roles in inflammatory diseases such as IBD.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Matthew Hepworth (Supervisor) & Mark Travis (Supervisor)