Letter | Published:

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

Nature volume 554, pages 373377 (15 February 2018) | Download Citation

Abstract

Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases1,2,3,4. 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 pathobionts4,5,6. 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.

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Acknowledgements

We thank S. Y. Kim and the NYU Rodent Genetic Engineering Laboratory (RGEL) for generating TCR transgenic mice, A. Heguy and colleagues at the NYU School of Medicine’s Genome Technology Center (GTC) for preparation of RNA-seq libraries and RNA sequencing, the NIH Tetramer Core Facility for generating MHC class II tetramers, K. Murphy for providing the 58αβ hybridoma line, D. E. Levy for providing the Stat3fl/fl;Cd4cre mice, J. Fox for providing the H. hepaticus strain, P. Dash and P. G. Thomas for advice on single-cell TCR cloning, and J. A. Hall, J. Muller and J. Lafaille for suggestions on the manuscript. The Experimental Pathology Research Laboratory of NYU Medical Center is supported by National Institutes of Health Shared Instrumentation grants S10OD010584-01A1 and S10OD018338-01. The GTC is partially supported by the Cancer Center Support grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work was supported by the Irvington Institute fellowship program of the Cancer Research Institute (M.X.); the training program in Immunology and Inflammation 5T32AI100853 (M.P.); the Helen and Martin Kimmel Center for Biology and Medicine (D.R.L.); the Colton Center for Autoimmunity (D.R.L.); and National Institutes of Health grant R01DK103358 (R.B. and D.R.L.). D.R.L. is an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Mo Xu
    •  & Maria Pokrovskii

    These authors contributed equally to this work.

Affiliations

  1. Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.

    • Mo Xu
    • , Maria Pokrovskii
    • , Christy Au
    • , Carolina Galan
    •  & Dan R. Littman
  2. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.

    • Yi Ding
  3. Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10003, USA.

    • Ren Yi
    •  & Richard Bonneau
  4. The Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.

    • Christy Au
    •  & Dan R. Littman
  5. Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.

    • Oliver J. Harrison
    •  & Yasmine Belkaid
  6. NIAID Microbiome Program, NIH, Bethesda, Maryland 20892, USA.

    • Yasmine Belkaid
  7. Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA.

    • Richard Bonneau
  8. Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, New York 10010, USA.

    • Richard Bonneau

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Contributions

M.X. and M.P. designed and performed all experiments and analysed the data. Y.D. performed blinded histology scoring on colitis sections. C.A. and C.G. assisted with in vivo and in vitro experiments. R.Y. and M.P. performed RNA-seq analysis. O.J.H. and Y.B. analysed the Gata3Treg mouse phenotype. R.B. supervised RNA-seq analysis. M.X., M.P. and D.R.L. wrote the manuscript with input from the co-authors. D.R.L. supervised the research and contributed to experimental design.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan R. Littman.

Reviewer Information Nature thanks C. Ohnmacht and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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https://doi.org/10.1038/nature25500

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