Naturally Arising Human CD4 T-Cells That Recognize Islet Autoantigens and Secrete Interleukin-10 Regulate Proinflammatory T-Cell Responses via Linked Suppression
- Timothy I.M. Tree1,2,
- Jennifer Lawson1,
- Hannah Edwards1,
- Ania Skowera1,2,
- Sefina Arif1,
- Bart O. Roep3 and
- Mark Peakman1,2
- 1Department of Immunobiology, King's College London, Guy's Hospital, London, U.K.;
- 2Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; and
- 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.
- Corresponding author: Timothy Tree, .
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.
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- Received April 6, 2009.
- Accepted March 1, 2010.
- © 2010 by the American Diabetes Association.
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