Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes
Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes
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DOI：
10.1073/pnas.0508621102
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发表时间：
2005-12-20
影响因子：
11.1
通讯作者：
Roep, BO
中科院分区：
文献类型：
--
作者：
Pinkse, GGM;Tysma, OHM;Roep, BO
1型糖尿病是一种T细胞介导的自身免疫性疾病，胰岛素是与β细胞破坏相关的自身免疫反应的重要靶点。破坏的机制仍不清楚。在这里，我们提供了CD8T细胞自身反应性与1型糖尿病胰岛移植受者反复的自身免疫和13细胞功能丧失相关的证据。我们首次鉴定了一种胰岛素B链肽(insB10-18)，它与大多数1型糖尿病患者表达的人类白细胞抗原A2(*0201)具有非凡的结合亲和力。接下来，我们证明了这种多肽是由构成蛋白酶体和免疫蛋白酶体自然加工的，并通过多肽转运蛋白Tan转移到内质网，从而与内质网中的HLA-A2结合并呈现在细胞表面。用该多肽体外刺激健康供者外周血单核细胞，分离出特异性识别表达胰岛素B链多肽的靶细胞的CD8T细胞。HL A-A2(insB10-18)四聚体染色显示，在1型糖尿病患者中，自身反应性CD8T细胞的检测与胰岛移植后复发的自身免疫和移植物失败有很强的相关性。我们证明CD8T细胞自身反应与人类1型糖尿病中的β细胞破坏有关。
Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with beta cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of 13 cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAN to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLA-A2(insB10-18) tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with beta cell destruction in type 1 diabetes in humans.