Naturally Arising Human CD4 T-Cells That Recognize Islet Autoantigens and Secrete Interleukin-10 Regulate Proinflammatory T-Cell Responses via Linked Suppression

  1. Mark Peakman1,2
  1. 1Department of Immunobiology, King's College London, Guy's Hospital, London, U.K.;
  2. 2Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; and
  3. 3National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's & St. Thomas' National Health Service (NHS) Foundation Trust and King's College London, London, U.K.
  1. Corresponding author: Timothy Tree, timothy.tree{at}kcl.ac.uk.

Abstract

OBJECTIVE Regulatory T-cells (Tregs) recognizing islet autoantigens are proposed as a key mechanism in the maintenance of self-tolerance and protection from type 1 diabetes. To date, however, detailed information on such cells in humans, and insight into their mechanisms of action, has been lacking. We previously reported that a subset of CD4 T-cells secreting high levels of the immunosuppressive cytokine interleukin-10 (IL-10) is significantly associated with late onset of type 1 diabetes and is constitutively present in a majority of nondiabetic individuals. Here, we test the hypothesis that these T-cells represent a naturally generated population of Tregs capable of suppressing proinflammatory T-cell responses.

RESEARCH DESIGN AND METHODS We isolated and cloned islet-specific IL-10–secreting CD4+ T-cells from nondiabetic individuals after brief ex vivo exposure to islet autoantigens using cytokine capture technology and examined their phenotype and regulatory potential.

RESULTS Islet-specific IL-10+ CD4 T-cells are potent suppressors of Th1 effector cells, operating through a linked suppression mechanism in which there is an absolute requirement for the cognate antigen of both the regulatory and effector T-cells to be presented by the same antigen-presenting cell (APC). The regulatory T-cells secrete perforin and granzymes, and suppression is associated with the specific killing of APCs presenting antigen to effector T-cells.

CONCLUSIONS This hitherto undescribed population of islet autoantigen–specific Tregs displays unique characteristics that offer exquisite specificity and control over the potential for pathological autoreactivity and may provide a suitable target with which to strengthen β-cell–specific tolerance.

Footnotes

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  • Received April 6, 2009.
  • Accepted March 1, 2010.

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  1. Diabetes vol. 59 no. 6 1451-1460
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