Constitutive androstane receptor directs T cell adaptation to bile acids in the small intestine
2020
Bile acids (BAs) are fundamental lipid emulsifying metabolites synthesized in hepatocytes and maintained via enterohepatic circulation between the liver and ileum. Because they are lipophilic, BAs can be cytotoxic in enterohepatic tissues and several nuclear receptors are now recognized for suppressing BA toxicity in hepatocytes and enterocytes. By contrast, it remains unclear how mucosal immune cells protect themselves from high BA concentrations in the small intestine. We previously showed that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to prevent BA toxicity and suppress Crohns disease-like small bowel inflammation. Here, we identify the BA- and xenobiotic-sensing nuclear receptor, constitutive androstane receptor (CAR/NR1I3), as a regulator of MDR1 expression in mucosal T cells. CAR expression increased in Teff cells during mucosal inflammation and promoted large-scale transcriptional reprogramming in the small intestine lamina propria (siLP). CAR-dependent gene expression in siLP Teff cells shared features with that in hepatocytes, and involved the induction of detoxifying enzymes and transporters, but also the key anti-inflammatory cytokine, Il10. CAR-deficiency in Teff cells exacerbated, whereas pharmacologic CAR activation suppressed, BA-driven ileitis in T cell-reconstituted Rag-/- mice. In addition, bile, though not major BA species per se, enhanced CAR transcriptional activity, and CAR-dependent gene expression in human CD4+ Th cells was restricted to a4+b7 integrin+CCR9+ Teff cells licensed for small bowel homing. These data implicate CAR in prompting a hepatocyte-like transcriptional response in mucosal T cells that detoxifies BAs and enforces small bowel immune homeostasis. Pharmacologic activation of this program may offer an unexpected strategy to treat small bowel Crohns disease.
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