C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

Mo Xu, Maria Pokrovskii, Yi Ding, Ren Yi, Christy Au, Oliver J. Harrison, Carolina Galan, Yasmine Belkaid, Richard Bonneau, Dan R. Littman

Research output: Contribution to journalArticle

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 (iTreg) cells that selectively restrain pro-inflammatory T helper 17 (TH17) 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 iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORγt inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 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 iTreg -TH17 homeostasis.

Original languageEnglish (US)
Pages (from-to)373-377
Number of pages5
JournalNature
Volume554
Issue number7692
DOIs
StatePublished - Feb 15 2018

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Th17 Cells
Helicobacter hepaticus
Regulatory T-Lymphocytes
Bacteria
T-Lymphocytes
Inflammatory Bowel Diseases
Interleukin-10
Microbial Genetics
Inflammation
Helicobacter
Microbiota
Large Intestine
Colitis
Autoimmune Diseases
Homeostasis
Transcription Factors

ASJC Scopus subject areas

  • General

Cite this

Xu, M., Pokrovskii, M., Ding, Y., Yi, R., Au, C., Harrison, O. J., ... Littman, D. R. (2018). C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature, 554(7692), 373-377. https://doi.org/10.1038/nature25500

C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. / Xu, Mo; Pokrovskii, Maria; Ding, Yi; Yi, Ren; Au, Christy; Harrison, Oliver J.; Galan, Carolina; Belkaid, Yasmine; Bonneau, Richard; Littman, Dan R.

In: Nature, Vol. 554, No. 7692, 15.02.2018, p. 373-377.

Research output: Contribution to journalArticle

Xu, M, Pokrovskii, M, Ding, Y, Yi, R, Au, C, Harrison, OJ, Galan, C, Belkaid, Y, Bonneau, R & Littman, DR 2018, 'C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont', Nature, vol. 554, no. 7692, pp. 373-377. https://doi.org/10.1038/nature25500
Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ et al. C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature. 2018 Feb 15;554(7692):373-377. https://doi.org/10.1038/nature25500
Xu, Mo ; Pokrovskii, Maria ; Ding, Yi ; Yi, Ren ; Au, Christy ; Harrison, Oliver J. ; Galan, Carolina ; Belkaid, Yasmine ; Bonneau, Richard ; Littman, Dan R. / C-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. In: Nature. 2018 ; Vol. 554, No. 7692. pp. 373-377.
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