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c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont
Open accessPublished version of a preprint
Abstract
Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt+FOXP3+ regulatory T (iT reg) cells that selectively restrain pro-inflammatory T helper 17 (T H 17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iT reg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic T H 17 cells. Inactivation of c-MAF in the T reg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iT reg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory T H 17 cells and spontaneous colitis. By contrast, RORγt inactivation in T reg cells had only a minor effect on the bacteria-specific T reg and T H 17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iT reg-T H 17 homeostasis.
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“This conclusion is further supported by the findings that GM-CSF+ T cells co-express a great variety of other cytokines including IL-2, IL-3, IL-4, IL-6, IL-13, IL-17A, IL-22, IFNγ, and TNF [33, 36, 76, 175].”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [33]
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“Hence, we propose GM-CSF expression as part of a general pathogenic program together with other pro-inflammatory molecules such as BHLHE40, IFNγ, and CXCR6 that can be induced across multiple T helper cell subsets [33, 38, 177].”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [33]
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Metadata
- Authors
- Xu, M., Pokrovskii, M., Ding, Y., Yi, R., Au, C., Harrison, O. J., Galan, C., Belkaid, Y., Bonneau, R., & Littman, D. R.
- Affiliations
- New York University (US)
- University of Rochester Medicine (US)
- Courant Institute of Mathematical Sciences (US)
- Howard Hughes Medical Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Littman, Dan R.
- ORCID
- Venue
- Nature
- Published
- 2018-02
- Volume
- 554
- Issue
- 7692
- Pages
- 373-377
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5814346
- OpenAlex
- W2786985471
- Cited by
- 498
- References
- 50
- Citations by year
- 2026: 33 · 2025: 63 · 2024: 45 · 2023: 66 · 2022: 64 · 2021: 64 · 2020: 65 · 2019: 66 · 2018: 32
- FWCI
- 24.38
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-02-05)
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- National Institutes of Health (1s10od018338-01, 1s10od010584-01a1)
- School of Medicine, New York University (P30CA016087)
- National Cancer Institute (P30CA016087)
- National Institute of Allergy and Infectious Diseases (T32AI100853)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103358)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- c-Maf, regulatory T cells, Helicobacter hepaticus, pathobionts, inflammatory bowel disease, Th17 cells, IL-10, RORγt, Foxp3, gut microbiota, immune tolerance, commensal bacteria, spontaneous colitis, IL-10-deficient mice, microbiota-targeted therapy
- MeSH terms
- Animals, Colitis, Female, Homeostasis, Immune Tolerance, Intestines, Male, Interleukin-10, Helicobacter hepaticus, T-Lymphocytes, Regulatory, Proto-Oncogene Proteins c-maf, Mice, Forkhead Transcription Factors, Host-Pathogen Interactions, Bioengineering, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells
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