Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3

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 primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages and early life. However, the mechanisms through which mature ILC3 are maintained within adult tissues are poorly understood. Here, we report that lymphoid tissue-inducer-like (LTi-like) ILC3 exhibit minimal turnover in the healthy adult intestinal tract, persist for extended periods of time, and display a quiescent phenotype. Strikingly, during enteric bacterial infection LTi-like ILC3 also exhibit negligible hematopoietic replenishment and remain non-proliferative, despite robustly producing cytokines. Survival of LTi-like ILC3 was found to be dependent upon the balance between the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein B-cell lymphoma-2 (Bcl-2) was required for the survival of LTi-like ILC3 ex vivo but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a tissue-resident, quiescent population that persist independently of hematopoietic replenishment to survive within the intestinal microenvironment.

Automated summary

Group 3 innate lymphoid cells (ILC3) play critical roles in immunity, barrier integrity and tissue homeostasis in the gastrointestinal tract. They are primarily tissue-resident cells, present from embryonic stages and persist into adulthood. However, the mechanisms of how mature ILC3 are maintained in adult tissues are poorly understood. This study demonstrates that lymphoid tissue-inducer-like (LTi-like) ILC3 are a quiescent population that persist for extended periods of time in the healthy adult intestinal tract. During bacterial infection, LTi-like ILC3 exhibit minimal hematopoietic replenishment and remain non-proliferative, while producing cytokines. Survival of LTi-like ILC3 is dependent on the balance between metabolic activity and anti-apoptotic programs. The pro-survival protein Bcl-2 is required for their survival, but can be partially dispensable if mitochondrial respiration is inhibited. In conclusion, this study highlights the importance of LTi-like ILC3 as a tissue-resident population that can survive independently in the intestinal microenvironment.