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Human gut-specific homeostatic dendritic cells are generated from blood precursors by the gut microenvironment

Authors

  • Elizabeth R. Mann PhD,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
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    • The first two authors contributed equally to this work.

  • David Bernardo PhD,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
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    • The first two authors contributed equally to this work.

  • Hafid Omar Al-Hassi PhD,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
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  • Nicholas R. English MIBiol,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
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  • Susan K. Clark MD,

    1. St. Mark's Hospital, North West London Hospitals NHS Trust, Harrow, UK
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  • Neil E. McCarthy PhD,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
    2. Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK
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  • Andrew N. Milestone MRCP,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
    2. St. Mark's Hospital, North West London Hospitals NHS Trust, Harrow, UK
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  • Stella A. Cochrane PhD,

    1. SEAC, Unilever Colworth, Bedford, UK
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  • Ailsa L. Hart PhD,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
    2. St. Mark's Hospital, North West London Hospitals NHS Trust, Harrow, UK
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  • Andrew J. Stagg PhD,

    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
    2. Centre for Immunology and Infectious Disease, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK
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  • Stella C. Knight PhD

    Corresponding author
    1. Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK
    • Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Level 7W St. Mark's Hospital, Watford Road, Harrow, HA1 3UJ, UK
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  • Supported by BBSRC, Unilever, FP7-people-IEF-2008-235993, St Mark's Foundation.

Abstract

Background:

Dendritic cells (DC) dictate not only the type of T-cell immunity, but also homing patterns of T cells in mice. In humans, we characterized normal human gut DC and tested whether gut-specific homeostatic DC could be generated from blood precursors by factors in the gut microenvironment.

Methods:

We characterized the phenotype and function of healthy human gut DC compared with blood and skin DC, and studied whether conditioning of blood DC in the presence of colonic biopsy supernatants (Bx-SN) induced gut-like phenotype and functions.

Results:

Blood DC mostly expressed both gut and skin homing markers, indicating potential to migrate to both major immune surface organs, and induced multi-homing T cells. However, DC within gut or skin did not demonstrate this multi-homing phenotype, were tissue-specific, and induced tissue-specific T cells. Human gut DC were less stimulatory for allogeneic T cells than their dermal and blood counterparts. Human blood DC cultured in vitro lost homing marker expression. Conditioning of human enriched blood DC with colonic Bx-SN from healthy controls induced a gut-homing phenotype and a homeostatic profile. Moreover, Bx-SN-conditioned DC demonstrated a restricted T-cell stimulatory capacity and preferentially induced gut-specific T cells. Retinoic acid and transforming growth factor beta (TGF-β) mediated the acquisition of the gut-homing and homeostatic properties, respectively, induced by colonic Bx-SN on blood enriched DC.

Conclusions:

Tissue-specific factors manipulate immunity via modulating characteristics of DC and may provide tools to generate tissue-specific immunotherapy. (Inflamm Bowel Dis 2011;)

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