BACH2 controls ILC3 function via PPARγ-dependent mitochondrial metabolism.

Group 3 innate lymphoid cells (ILC3s) play an essential role in maintaining intestinal barrier immunity. Dysfunction of ILC3s contributes to the pathogenesis of inflammatory bowel disease (IBD), whereas the mechanisms underlying ILC3 regulation remain incompletely understood. Here, we report that the transcription factor BTB domain and CNC homolog 2 (BACH2) represents an important regulator of intestinal ILC3s. ILC3s from IBD patients exhibited reduced BACH2 expression compared with those from healthy donors. Conditional ablation of BACH2 in ILC3s impaired their function, thereby exacerbating the severity of murine colitis. Mechanistically, BACH2 enhanced mitochondrial oxidative phosphorylation in ILC3s in a peroxisome proliferator-activated receptor γ (PPARγ)-dependent manner. PPARγ was identified as a direct transcriptional target of BACH2 in ILC3s. Notably, pharmacological activation of PPARγ with rosiglitazone restored ILC3 function and ameliorated colitis in BACH2-deficient mice. These observations demonstrate that the presence of BACH2-PPARγ signaling in ILC3s protects against colitis.