Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion.
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion.
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DOI：
10.1126/science.aad2791
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发表时间：
2016-02-12
期刊：
影响因子：
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通讯作者：
Haskins K
中科院分区：
文献类型：
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作者：
Delong T;Wiles TA;Baker RL;Bradley B;Barbour G;Reisdorph R;Armstrong M;Powell RL;Reisdorph N;Kumar N;Elso CM;DeNicola M;Bottino R;Powers AC;Harlan DM;Kent SC;Mannering SI;Haskins K
1型糖尿病（T1D）是由T细胞介导的胰岛素产生β细胞的破坏引起的。CD4 T细胞应答在β细胞破坏中起核心作用，但致病性CD4 T细胞识别的表位的身份仍然未知。为了解决这个问题，我们使用了一组从非肥胖糖尿病（NOD）小鼠分离的糖尿病触发CD4 T细胞克隆。在这里，我们表明这些致病性CD4 T细胞靶向肽配体，这些肽配体是通过胰岛素原肽与β细胞分泌颗粒中存在的其他肽共价交联形成的。这些杂合胰岛素肽（HIP）对CD4 T细胞具有高度抗原性，并且可以通过质谱法在β细胞中检测到。来自两名患有T1D的器官供体的残余胰岛的CD4 T细胞也识别HIP。自身反应性T细胞靶向杂交肽的发现可能解释了T1D中免疫耐受是如何被打破的。
Type 1 diabetes (T1D) is caused by T cell mediated destruction of the insulin-producing β cells. CD4 T cell responses play a central role in β-cell destruction but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. To address this we used a panel of diabetes triggering CD4 T cell clones isolated from non-obese diabetic (NOD) mice. Here we show that these pathogenic CD4 T cells target peptide ligands that are formed by covalent crosslinking of proinsulin peptides to other peptides present in β-cell secretory granules. These hybrid insulin peptides (HIPs) are highly antigenic for CD4 T cells and can be detected by mass spectrometry in β-cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. The discovery that autoreactive T cells target hybrid peptides may explain how immune tolerance is broken in T1D.