Article | Published:

Classical dendritic cells are required for dietary antigen–mediated induction of peripheral Treg cells and tolerance

Nature Immunology volume 17, pages 545555 (2016) | Download Citation

Abstract

Oral tolerance prevents pathological inflammatory responses to innocuous foreign antigens by peripheral regulatory T cells (pTreg cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure for the 'instruction' of naive CD4+ T cells to differentiate into pTreg cells has not been defined. Using myeloid lineage–specific APC depletion in mice, we found that monocyte-derived APCs were dispensable, while classical dendritic cells (cDCs) were critical, for pTreg cell induction and oral tolerance. CD11b cDCs from the gut-draining lymph nodes efficiently induced pTreg cells and, conversely, loss of transcription factor IRF8–dependent CD11b cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in the induction of pTreg cells and their redundancy during the development of oral tolerance.

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Acknowledgements

We thank M. Amoury and L. Cohn for thoughts for the beginning of the project; M. Nussenzweig (The Rockefeller University) for Csf1rLsL-DTR, zDCDTR and zDCCre knock-in mice and conceptual input; S. Mazmanian (California Institute of Technology) for germ-free C57BL/6 mice; B. Reis and V. Pedicord for assistance in mouse-dissection experiments, critical discussions and help in preparing the manuscript; K. Velinzon and N. Thomas for assistance in cell sorting; The Rockefeller University Genomics Center; A. Rogoz, T. Rendon, S. Gonzalez and the Rockefeller University Comparative Bioscience Center for animal care and genotyping; and the New York University histology core for lung histological staining. Supported by the Swiss National Foundation (D.E.), The US National Institutes of Health (1R56AI119062 to D.M.) and the Leona M. and Harry B. Helmsley Charitable Trust (D.E. and D.M.).

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Affiliations

  1. Laboratory of Mucosal Immunology, The Rockefeller University, New York, New York, USA.

    • Daria Esterházy
    • , Mariya London
    • , Veronica Jove
    •  & Daniel Mucida
  2. Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.

    • Jakob Loschko
    •  & Thiago Y Oliveira

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Contributions

D.E. designed the study, performed the experiments (unless stated otherwise below) and wrote the manuscript; J.L. generated the zDCCre mice and backcrossed them onto the Irf8fl/fl background, carried out their hematopoietic characterization (Fig. 7) and substantially contributed to the design of experiments; M.L. and V.J. contributed substantially to the establishment of oral-tolerance protocols and to the oral-tolerance experiments; T.Y.O. performed the bioinformatics analysis of the RNA-seq experiments; and D.M. initiated, designed and supervised the study, performed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel Mucida.

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https://doi.org/10.1038/ni.3408

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