The Aryl Hydrocarbon Receptor Repressor Prevents Oxidative Stress and Ferroptosis of Intestinal Intraepithelial Lymphocytes

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here we show that AHRR is vital to sustain intestinal intraepithelial lymphocytes (IEL). Fewer IEL of all types were present in the absence of AHRR. Single cell RNA sequencing (scRNAseq) revealed an oxidative cell stress profile in Ahrr–/– IEL. Ahrr deficiency unleashed AHR-induced expression of CYP1A1, an oxidative enzyme that generates reactive oxygen species; this resulted in elevated intracellular content of reactive oxygen species, lipid peroxidation and ferroptosis in Ahrr–/– IEL. Dietary supplementation with selenium or Vitamin-E (Vit-E) to restore redox homeostasis rescued Ahrr–/– IEL. Loss of IEL in Ahrr deficient mice caused susceptibility to Clostridium difficile infection and dextran sodium sulfate-induced colitis. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IEL to preserve intestinal immune responses. CD3+ small intestinal IEL were sorted from two Ahrr KO mice and two WT littermate controls.