Abstract

Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8+, CD103+, CD11b+ and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.

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Acknowledgements

We thank colleagues of the ImmGen Project, especially the technical team, including M. Painter, J. Ericson and S. Davis, for contributions; C. Benoist for contributions to the design and writing of the manuscript; and eBioscience and Affymetrix for support of the ImmGen Project. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R24 AI072073 to the ImmGen Project (led by C. Benoist); AI080884 and HL086899 to M.M.; JDRF172010770 and DP2DK083052-01 to B.D.B.; DK074500 and AI045757 to S.J.T.; HL69438, DK056638, HL097819 and HL097700 to P.S.F.; and U54CA149145 to V.J.).

Author information

Author notes

    • Vladimir Jojic

    Present address: Department of Computer Science, UNC, Chapel Hill, North Carolina, USA.

Affiliations

  1. Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA.

    • Jennifer C Miller
    • , Brian D Brown
    • , Emmanuel L Gautier
    • , Marylene Leboeuf
    • , Julie Helft
    • , Daigo Hashimoto
    • , Andrew Chow
    • , Jeremy Price
    • , Melanie Greter
    • , Milena Bogunovic
    • , Gwendalyn J Randolph
    •  & Miriam Merad
  2. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Jennifer C Miller
    • , Marylene Leboeuf
    • , Julie Helft
    • , Daigo Hashimoto
    • , Andrew Chow
    • , Jeremy Price
    • , Melanie Greter
    • , Milena Bogunovic
    •  & Miriam Merad
  3. Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, USA.

    • Brian D Brown
    • , Ariella Cohain
    •  & Gaurav Pandey
  4. Broad Institute, Cambridge, Massachusetts, USA.

    • Tal Shay
  5. Department of Regenerative Biology, Mount Sinai School of Medicine, New York, New York, USA.

    • Emmanuel L Gautier
    •  & Gwendalyn J Randolph
  6. Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, Missouri, USA.

    • Emmanuel L Gautier
    •  & Gwendalyn J Randolph
  7. Computer Science Department, Stanford University, Stanford, California, USA.

    • Vladimir Jojic
    •  & Melanie Greter
  8. Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

    • Kutlu G Elpek
    • , Angelique Bellemare-Pelletier
    •  & Shannon J Turley
  9. Albert Einstein College of Medicine, Bronx, New York, USA.

    • Andrew Chow
    •  & Paul S Frenette
  10. Mount Sinai Hospital, New York, New York, USA.

    • Emmanuel L Gautier
    • , Claudia Jakubzick
    • , Gwendalyn J Randolph
    • , Jennifer Miller
    • , Brian Brown
    •  & Miriam Merad
  11. Department of Pathology & Immunology, Washington University, St. Louis, Missouri, USA.

    • Emmanuel L Gautier
    •  & Gwendalyn J Randolph
  12. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.

    • Adam J Best
    • , Jamie Knell
    •  & Ananda Goldrath
  13. Computer Science Department, Stanford University, Stanford, California, USA.

    • Vladimir Jojic
    • , Daphne Koller
    •  & Taras Kreslavsky
  14. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Nadia Cohen
    • , Patrick Brennan
    •  & Michael Brenner
  15. Broad Institute, Cambridge, Massachusetts, USA.

    • Tal Shay
    •  & Aviv Regev
  16. Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

    • Anne Fletcher
    • , Kutlu Elpek
    • , Angelique Bellemare-Pelletier
    • , Deepali Malhotra
    •  & Shannon Turley
  17. Computer Science Department, Brown University, Providence, Rhode Island, USA.

    • Radu Jianu
    •  & David Laidlaw
  18. Department of Biomedical Engineering, Howard Hughes Medical Institute, Boston University, Boston, Massachusetts, USA.

    • Jim Collins
  19. University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Kavitha Narayan
    • , Katelyn Sylvia
    •  & Joonsoo Kang
  20. Department of Stem Cell and Regenerative Biology, Harvard University, and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, Massachusetts, USA.

    • Roi Gazit
    •  & Derrick J Rossi
  21. Joslin Diabetes Center, Boston, Massachusetts, USA.

    • Francis Kim
    • , Tata Nageswara Rao
    •  & Amy Wagers
  22. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Susan A Shinton
    •  & Richard R Hardy
  23. Department of Medicine, Boston University, Boston, Massachusetts, USA.

    • Paul Monach
  24. Department of Microbiology & Immunology, University of California San Francisco, San Francisco, California, USA.

    • Natalie A Bezman
    • , Joseph C Sun
    • , Charlie C Kim
    •  & Lewis L Lanier
  25. Department of Microbiology & Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA.

    • Tracy Heng
    • , Michio Painter
    • , Jeffrey Ericson
    • , Scott Davis
    • , Diane Mathis
    •  & Christophe Benoist

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Contributions

J.C.M. did experiments and wrote the paper; M.M. designed experiments and wrote the paper; B.D.B. provided intellectual input, did computational analyses and helped write the paper; T.S. did computation analyses and identified all modules; E.L.G. purified macrophage populations and provided intellectual input; V.J. did computation analyses and, together with T.S., designed Ontogenet; A.C. and G.P. did computation analyses; M.L. did experiments; K.G.E., J.H., D.H., A.C. and J.P. purified DC populations; M.G. purified macrophage populations; M.B. and A.B.-P. purified DC and macrophage populations; P.S.F. provided intellectual input; and G.J.R. and S.J.T. provided intellectual input for experimental design.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Miriam Merad.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7

Excel files

  1. 1.

    Supplementary Table 1

    Comparison of DC subsets transcriptomes

  2. 2.

    Supplementary Table 2

    Comparison of the transcriptome of migratory DC and tissue resident DC

About this article

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DOI

https://doi.org/10.1038/ni.2370

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