The xenobiotic transporter Mdr1 permits T cell adaptation to mucosa-associated bile acids in the ileum

Autor: Mark S Sundrud, Wei Cao, Hisako Kayama, Mei Lan Chen, Amber Delmas, Amy Sun, Sang Yong Kim, Kelly McKevitt, Erumbi S. Rangarajan, Amanda P. Beck, Angelos Oikonomopoulos, Precious N. Lacey, Gustavo J Martinez, Tina Izard, Robin G Lorenz, Alex Rodriguez-Palacios, Fabio Cominelli, Maria T Abreu, Daniel W. Hommes, Sergei B Koralov, Kiyoshi Takeda
Rok vydání: 2017
Předmět:
Zdroj: The Journal of Immunology. 198:65.14-65.14
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.198.supp.65.14
Popis: 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.
Databáze: OpenAIRE
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