CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner

Authors

  • Behdad Afzali,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Peter J. Mitchell,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Francis C. Edozie,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Giovanni A.M. Povoleri,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Sophie E. Dowson,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Laura Demandt,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Gina Walter,

    1. Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, King's Health Partners, Guy's Hospital, London, UK
    2. Department of Immunobiology, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • James B. Canavan,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Cristiano Scotta,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Bina Menon,

    1. Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, King's Health Partners, Guy's Hospital, London, UK
    2. Department of Immunobiology, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Prabhjoat S. Chana,

    1. Flow Cytometry Core Facility at the National Institute for Health Research Guy's and St Thomas’ NHS Foundation Trust/King's College London comprehensive Biomedical Research Centre, Guy's Hospital, London, UK
    Search for more papers by this author
  • Wafa Khamri,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Shahram Y. Kordasti,

    1. Department of Hematological Medicine, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Susanne Heck,

    1. Flow Cytometry Core Facility at the National Institute for Health Research Guy's and St Thomas’ NHS Foundation Trust/King's College London comprehensive Biomedical Research Centre, Guy's Hospital, London, UK
    Search for more papers by this author
  • Bodo Grimbacher,

    1. Department of Immunology and Molecular Pathology, Royal Free Hospital, University College, London, UK
    Search for more papers by this author
  • Timothy Tree,

    1. Department of Immunobiology, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Andrew P. Cope,

    1. Academic Department of Rheumatology, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Leonie S. Taams,

    1. Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, King's Health Partners, Guy's Hospital, London, UK
    2. Department of Immunobiology, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
  • Robert I. Lechler,

    1. Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Susan John,

    Corresponding author
    • Department of Immunobiology, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Giovanna Lombardi

    Corresponding author
    • Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
    Search for more papers by this author

Full correspondence: Dr. Susan John, Department of Immunobiology, 2nd Floor Borough Wing, Guys Hospital, London SE1 9RT, UK.

Fax: +44-0-2071883385

e-mail: susan.john@kcl.ac.uk

Additional correspondence: Prof. Giovanna Lombardi, Immunoregulation Laboratory, MRC Centre for Transplantation, 5th floor Bermondsey Wing, Guy's Hospital, London, UK, SE1 9RT

e-mail: giovanna.lombardi@kcl.ac.ukF

Abstract

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are “plastic”, and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. “IL-17 potential” is restricted to population III (CD4+CD25hiCD127loCD45RA) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161+ population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.

Ancillary