The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids

Immunity. 2017 Dec 19;47(6):1182-1196.e10. doi: 10.1016/j.immuni.2017.11.012.

Abstract

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.

Keywords: Crohn’s disease; IBD; MDR1; T cells; Th1; Th17; bile acids; cholestyramine; ileitis.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / immunology*
  • Acridines / pharmacology
  • Adult
  • Animals
  • Bile Acids and Salts / immunology*
  • Bile Acids and Salts / metabolism
  • Bile Acids and Salts / pharmacology
  • Biological Transport
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Crohn Disease / genetics
  • Crohn Disease / immunology*
  • Crohn Disease / pathology
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Homeostasis / immunology
  • Humans
  • Ileitis / genetics
  • Ileitis / immunology*
  • Ileitis / pathology
  • Ileum / immunology
  • Ileum / pathology
  • Immunity, Mucosal
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Oxidative Stress
  • Signal Transduction
  • Tetrahydroisoquinolines / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acridines
  • Bile Acids and Salts
  • Homeodomain Proteins
  • Tetrahydroisoquinolines
  • RAG-1 protein
  • Elacridar