Author
Listed:
- Clarissa Campbell
(Memorial Sloan Kettering Cancer Center)
- Peter T. McKenney
(Memorial Sloan Kettering Cancer Center
Boehringer Ingelheim Pharmaceuticals)
- Daniel Konstantinovsky
(Yale University)
- Olga I. Isaeva
(Skolkovo Institute of Science and Technology
BostonGene LLC)
- Michail Schizas
(Memorial Sloan Kettering Cancer Center)
- Jacob Verter
(Memorial Sloan Kettering Cancer Center)
- Cheryl Mai
(Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD–PhD Program)
- Wen-Bing Jin
(Cornell University)
- Chun-Jun Guo
(Cornell University)
- Sara Violante
(Memorial Sloan Kettering Cancer Center)
- Ruben J. Ramos
(Memorial Sloan Kettering Cancer Center)
- Justin R. Cross
(Memorial Sloan Kettering Cancer Center)
- Krishna Kadaveru
(Boehringer Ingelheim Pharmaceuticals)
- John Hambor
(Boehringer Ingelheim Pharmaceuticals)
- Alexander Y. Rudensky
(Memorial Sloan Kettering Cancer Center
BostonGene LLC
Cornell University
Memorial Sloan Kettering Cancer Center)
Abstract
Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)2–4. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced Treg (pTreg) cells5–7, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids8 with a range of physiological functions9. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pTreg cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of Treg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing Treg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.
Suggested Citation
Clarissa Campbell & Peter T. McKenney & Daniel Konstantinovsky & Olga I. Isaeva & Michail Schizas & Jacob Verter & Cheryl Mai & Wen-Bing Jin & Chun-Jun Guo & Sara Violante & Ruben J. Ramos & Justin R., 2020.
"Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells,"
Nature, Nature, vol. 581(7809), pages 475-479, May.
Handle:
RePEc:nat:nature:v:581:y:2020:i:7809:d:10.1038_s41586-020-2193-0
DOI: 10.1038/s41586-020-2193-0
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Cited by:
- Lulu Sun & Yi Zhang & Jie Cai & Bipin Rimal & Edson R. Rocha & James P. Coleman & Chenran Zhang & Robert G. Nichols & Yuhong Luo & Bora Kim & Yaozong Chen & Kristopher W. Krausz & Curtis C. Harris & A, 2023.
"Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer,"
Nature Communications, Nature, vol. 14(1), pages 1-18, December.
- David J. Dittmar & Franziska Pielmeier & Nicholas Strieder & Alexander Fischer & Michael Herbst & Hanna Stanewsky & Niklas Wenzl & Eveline Röseler & Rüdiger Eder & Claudia Gebhard & Lucia Schwarzfisch, 2024.
"Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease,"
Nature Communications, Nature, vol. 15(1), pages 1-16, December.
- Lei Zhang & Li Jiang & Liang Yu & Qin Li & Xiangjun Tian & Jingquan He & Ling Zeng & Yuqin Yang & Chaoran Wang & Yuhan Wei & Xiaoyue Jiang & Jing Li & Xiaolu Ge & Qisheng Gu & Jikun Li & Di Wu & Antho, 2022.
"Inhibition of UBA6 by inosine augments tumour immunogenicity and responses,"
Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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