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
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
引用
收藏
页码:1451 / 1460
页数:10
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