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The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids
Open accessAbstract
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.
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“Previous reports have shown that CD4+ T cells require the MDR1 efflux transporter (encoded by Abcb1a/b in mice) to survive in BA-rich intestinal tissues (26).”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [26]
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Metadata
- Authors
- Cao, W., Kayama, H., Chen, M. L., Delmas, A., Sun, A., Kim, S. Y., Rangarajan, E. S., McKevitt, K., Beck, A. P., Jackson, C. B., Crynen, G., Oikonomopoulos, A., Lacey, P. N., Martinez, G. J., Izard, T., Lorenz, R. G., Rodriguez-Palacios, A., Cominelli, F., Abreu, M. T., Hommes, D. W., Koralov, S. B., Takeda, K., & Sundrud, M. S.
- Affiliations
- Scripps Research Institute (US)
- The University of Osaka (JP)
- New York University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- University of Alabama at Birmingham (US)
- Case Western Reserve University (US)
- University of Miami (US)
- Corresponding author
- Sundrud, Mark S.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 47
- Issue
- 6
- Pages
- 1182-1196.e10
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5741099
- OpenAlex
- W2777277663
- Cited by
- 102
- References
- 52
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 11 · 2023: 11 · 2022: 15 · 2021: 19 · 2020: 14 · 2019: 6 · 2018: 8 · 2017: 1
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-03-17)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- TSRI Florida
- State of Florida
- National Institute of Allergy and Infectious Diseases (R21AI119728, R21AI124129)
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK099076-07, P01DK071176)
- National Heart, Lung, and Blood Institute (RO1HL125816)
- Crohn’s and Colitis Foundation of America (422515, 3786, 26971)
- Broad Medical Foundation (IBD-0389R)
- Colton Center for Autoimmunity
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (JPMJCR10J2)
- Ministry of Education, Culture, Sports, Science and Technology (T15K15152, A15H02511)
- Ministry of Health, Labour, and Welfare (201324001B)
- Lotte Research Promotion Grant
- Nagao Memorial Fund
- 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
- WebMD Health
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- MDR1, P-glycoprotein, CD4+ T cells, T cell homeostasis, bile acid conjugates, ileum, Crohn's disease, intestinal immune homeostasis, oxidative stress, gut microbiota, Rag1-deficient mice, ileal mucosa
- MeSH terms
- Acridines, Adult, Animals, Bile Acids and Salts, Biological Transport, Crohn Disease, Disease Models, Animal, Female, Gene Expression Regulation, Homeostasis, Humans, Ileitis, Ileum, Intestinal Mucosa, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Signal Transduction, CD4-Positive T-Lymphocytes, Oxidative Stress, Homeodomain Proteins, Immunity, Mucosal, ATP Binding Cassette Transporter, Subfamily B, Member 1, Tetrahydroisoquinolines, Mice
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