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Diabetes. 2010 Jun;59(6):1451-60. doi: 10.2337/db09-0503. Epub 2010 Mar 18.

Naturally arising human CD4 T-cells that recognize islet autoantigens and secrete interleukin-10 regulate proinflammatory T-cell responses via linked suppression.

Author information

  • 1Department of Immunobiology, King's College London, Guy's Hospital, London, UK. timothy.tree@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 beta-cell-specific tolerance.

PMID:
20299476
PMCID:
PMC2874706
DOI:
10.2337/db09-0503
[PubMed - indexed for MEDLINE]
Free PMC Article
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