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Naturally Arising Human CD4 T-Cells That Recognize Islet Autoantigens and Secrete Interleukin-10 Regulate Proinflammatory T-Cell Responses via Linked Suppression
被引:82
作者:
Tree, Timothy I. M.
[1
,2
]
Lawson, Jennifer
[1
]
Edwards, Hannah
[1
]
Skowera, Ania
[1
,2
]
Arif, Sefina
[1
]
Roep, Bart O.
[3
]
Peakman, Mark
[1
,2
]
机构:
[1] Kings Coll London, Guys Hosp, Dept Immunobiol, London WC2R 2LS, England
[2] Leiden Univ, Med Ctr, Dept Immunohaematol & Blood Transfus, Leiden, Netherlands
[3] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Biomed Res Ctr, NIHR, London, England
来源:
关键词:
TRANSLATIONAL MINIREVIEW SERIES;
IMMUNOLOGICAL SELF-TOLERANCE;
AUTOIMMUNE-DISEASE;
DENDRITIC CELLS;
DIFFERENTIAL EXPRESSION;
GRANZYME-B;
ANTIGEN;
TYPE-1;
MICE;
INDUCTION;
D O I:
10.2337/db09-0503
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
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 (11,10) is significantly associated with late onset of type 1 diabetes and is constitutively present in a majority of nondiabetic 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 nondiabelie 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. Diabetes 59: 1451-1460, 2010
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页码:1451 / 1460
页数:10
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