The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function

Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues at mucosal surfaces and produce interleukin 17 (IL-13) and interleukin 22 (IL-22) to control infections and promote tissue homeostasis. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function remains unknown. Here we show that LKB1 is crucial for ILC3 homeostasis, cytokine production and mitochondrial function. ILC3-specific LKB1 deletion resulted in reduced ILC3 numbers and IL-22 production and a proportional increase in IL-17 production. LKB1-deficient ILC3s had decreased survival, dysregulated expression of ILC marker genes, mitochondrial disfunction with lipid accumulation. In vitro cultures with both inhibitors and activator of LKB1 downstream kinases showed that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through AMP-activated protein kinase (AMPK) and MAP/microtubule affinity-regulating kinases (MARKs), while salt-inducible kinases (SIKs) signaling restrains excessive IL-17 production. Our work reveals that metabolic regulation of enteric ILC3 function by a LKB1-dependent signaling network is crucial to promote intestinal immunity and tissue homeostasis.