Abstract
<jats:p>Constitutive androstane receptor (CAR, encoded by Nr1i3) is a nuclear xenobiotic receptor that mediates hepatic drug and bile acid metabolism. We previously identified CAR as also operating in CD4 T helper (Th) cells, where CAR dependent gene expression mitigates bile acid toxicity and promotes a Foxp3 negative IL10 positive type 1 regulatory (Tr1) like phenotype in the small intestine. Here, we show that CAR acts early and specifically during the priming of type 1 immune responses to stabilize Tr1 lineage commitment. CAR dependent Tr1 cells formed during type 1 (Th1 associated) but not type 3 (Th17 associated) intestinal inflammation. In vitro, IL27 upregulated CAR expression during naive Th cell activation, which contributed to Il10 induction. Single cell analysis revealed that naive Th cells primed with IL27 adopt a multipotent Th1/Tr1 precursor (THR1p) transcriptional state, which subsequently diverges into Th1 or Tr1 developmental trajectories. CAR transcriptional activity peaked in THR1p cells, upregulating Tr1 genes, including Il10, and repressing Th1 genes. Moreover, glucocorticoid receptor activation, which increases CAR expression in hepatocytes, synergized with IL27 to augment both CAR expression and CAR dependent Tr1 differentiation. Together, these results suggest that CAR acts in a lineage biased manner to enforce Tr1 mediated immune tolerance during type 1 intestinal inflammation, and this pathway is amplified by glucocorticoids.</jats:p>