Inflammatory T helper 17 cells in humans are distinguished by selective expression of MDR1 and are enriched in the gut of patients with Crohn’s disease.

CD4 T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1 mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

No abstract

Intestinal CD4+ T helper (TH) cells are subject to extensive regulation by microbiota. By contrast, it is not known whether or how TH cells interface with other, host-derived intestinal metabolites. Here we show that bile acids directly regulate mucosal TH cell function in the distal small intestine (i.e., ileum) via the xenobiotic transporter, Mdr1. Using both Mdr1-dependent dye efflux and a novel CRISPR-generated Mdr1 reporter mouse, we show that wild type RORγt+IL-17A+ (Th17) and RORγt-IFNγ+ (Th1) cells upregulate Mdr1 expression upon migration into the ileum. By contrast, germline ablation or shRNAmir-mediated knockdown of Mdr1 in Th17 and Th1 cells results in local dysfunction in the ileum, and these cells transfer Crohn’s disease-like ileitis in Rag1−/− hosts. Mdr1 enforces Th17 and Th1 cell survival and limits pro-inflammatory cytokine (TNFα, IFNγ) expression in the presence of conjugated bile acids (CBAs), which are actively reabsorbed through the ileal mucosa as a function of enterohepatic bile acid circulation. Accordingly, genetic or pharmacologic blockade of ileal CBA reabsorption restores Mdr1-deficient Th17 and Th1 cell homeostasis in ilea of transferred Rag1−/− hosts and rescues ileitis. In addition, MDR1 loss-of-function is evident in both ileitis-prone (SAMP1/YitFc) mice, and a subset of ileal Crohn’s disease patients. These data indicate that coordinated, local and druggable interactions between mucosal TH cells and mucosa-associated bile acids in the ileum contribute to intestinal immune homeostasis.