Constitutive androstane receptor directs developing Th1 cells towards the Tr1 lineage

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Abstract 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 (T H ) cells, where CAR-dependent gene expression mitigates bile acid toxicity and promotes a Foxp3 - IL-10 + 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 , IL-27 upregulated CAR expression during naïve T H cell activation, which contributed to Il10 induction. Single-cell analysis revealed that naïve T H cells primed with IL-27 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 IL-27 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.

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