@article{c9deaaf913f64346a90cb440888083b6,
title = "The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids",
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. The role of host-derived intestinal metabolites in mucosal immune regulation is poorly understood. Here, Cao et al. show that effector CD4+ T cells upregulate expression of the xenobiotic transporter, Mdr1, in the ileum to safeguard immune homeostasis, revealing an important immunologic consequence of ileal bile acid reabsorption.",
keywords = "Crohn's disease, IBD, MDR1, T cells, Th1, Th17, bile acids, cholestyramine, ileitis",
author = "Wei Cao and Hisako Kayama and Chen, {Mei Lan} and Amber Delmas and Amy Sun and Kim, {Sang Yong} and Rangarajan, {Erumbi S.} and Kelly McKevitt and Beck, {Amanda P.} and Jackson, {Cody B.} and Gogce Crynen and Angelos Oikonomopoulos and Lacey, {Precious N.} and Martinez, {Gustavo J.} and Tina Izard and Lorenz, {Robin G.} and Alex Rodriguez-Palacios and Fabio Cominelli and Abreu, {Maria T.} and Hommes, {Daniel W.} and Koralov, {Sergei B.} and Kiyoshi Takeda and Sundrud, {Mark S.}",
note = "Funding Information: We thank the Core Facilities at The Scripps Research Institute (TSRI) Florida for technical support and Dr. Paul Dawson for critical discussions. This work was funded by TSRI Florida via the State of Florida (to M.S.S.), the National Institute of Allergy and Infectious Diseases (R21AI119728, to M.S.S.; R21AI124129, to S.B.K.), the National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK099076-07, to M.T.A.; P01DK071176, to R.G.L.), the National Heart, Lung, and Blood Institute (RO1HL125816, to S.B.K.), the Crohn's and Colitis Foundation of America (#422515, to M.S.S.; #3786, to M.T.A.; #26971, to R.G.L.), the Broad Medical Foundation (#IBD-0389R, to M.T.A.), and the Colton Center for Autoimmunity (to S.B.K.), as well as the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (JPMJCR10J2, to K.T.); the Ministry of Education, Culture, Sports, Science and Technology (T15K15152 and A15H02511, to K.T.); and the Ministry of Health, Labour, and Welfare (201324001B, to K.T.). H.K. was supported by a Lotte Research Promotion Grant and the Nagao Memorial Fund. M.T.A. and D.W.H. have received research grants and consultancy fees from AbbVie, Amgen, Asana Medical, Ferring Pharmaceuticals, Focus Medical Communications, Genentech, Genova Diagnostics, GI Health Foundation, Gilead, GSK Holding Americas, Hospira, Janssen, Mucosal Health Board, Pfizer, Prometheus Laboratories, Prova Education, Sanofi Aventis, Shire, Takeda, UCB, and WebMD Health. M.S.S. and A.D. hold a provisional patent on screening IBD patients for MDR1 loss of function. Funding Information: We thank the Core Facilities at The Scripps Research Institute (TSRI) Florida for technical support and Dr. Paul Dawson for critical discussions. This work was funded by TSRI Florida via the State of Florida (to M.S.S.), the National Institute of Allergy and Infectious Diseases ( R21AI119728 , to M.S.S.; R21AI124129 , to S.B.K.), the National Institute of Diabetes and Digestive and Kidney Diseases ( 5R01DK099076-07 , to M.T.A.; P01DK071176 , to R.G.L.), the National Heart, Lung, and Blood Institute ( RO1HL125816 , to S.B.K.), the Crohn{\textquoteright}s and Colitis Foundation of America ( #422515 , to M.S.S.; #3786 , to M.T.A.; #26971 , to R.G.L.), the Broad Medical Foundation ( #IBD-0389R , to M.T.A.), and the Colton Center for Autoimmunity (to S.B.K.), as well as the Core Research for Evolutional Science and Technology , Japan Science and Technology Agency ( JPMJCR10J2 , to K.T.); the Ministry of Education, Culture, Sports, Science and Technology ( T15K15152 and A15H02511 , to K.T.); and the Ministry of Health, Labour, and Welfare ( 201324001B , to K.T.). H.K. was supported by a Lotte Research Promotion Grant and the Nagao Memorial Fund . M.T.A. and D.W.H. have received research grants and consultancy fees from AbbVie, Amgen, Asana Medical, Ferring Pharmaceuticals, Focus Medical Communications, Genentech, Genova Diagnostics, GI Health Foundation, Gilead, GSK Holding Americas, Hospira, Janssen, Mucosal Health Board, Pfizer, Prometheus Laboratories, Prova Education, Sanofi Aventis, Shire, Takeda, UCB, and WebMD Health. M.S.S. and A.D. hold a provisional patent on screening IBD patients for MDR1 loss of function. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = dec,
day = "19",
doi = "10.1016/j.immuni.2017.11.012",
language = "English (US)",
volume = "47",
pages = "1182--1196.e10",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}
