Journal
NATURE
Volume 576, Issue 7785, Pages 143-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1785-z
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Funding
- NIH [P30DK034854]
- Charles A. King Trust Fellowship
- Harvard Medical School Dean's Innovation Grant in the Basic and Social Sciences
- Howard Hughes Medical Institute
- National Institutes of Health [R01AI080885, R01 DK110559]
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Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (T(H)17 cells) or regulatory T cells (T-reg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of T(H)17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-gamma t (ROR gamma t) and isoalloLCA increased the differentiation of T-reg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of T-reg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase T-reg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced T(H)17 cell differentiation and increased T-reg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of T(H)17 and T-reg cells.
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