CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
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DOI：
10.1172/jci35449
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发表时间：
2008-10-01
影响因子：
15.9
通讯作者：
Peakman, Mark
中科院分区：
文献类型：
--
作者：
Skowera, Ania;Ellis, Richard J.;Peakman, Mark
β细胞破坏导致胰岛素缺乏、高血糖和临床1型糖尿病的最终途径尚不清楚。在这里，我们表明循环CTL可以通过识别葡萄糖调节表位来杀死β细胞。首先，我们通过从HLA-A2（具体地，由A*0201等位基因编码的蛋白质）分子洗脱，从人前胰岛素原信号肽中鉴定出2个天然加工的表位。这些加工是非常规的，既不需要蛋白酶体，也不需要与加工相关的转运蛋白（TAP）。然而，这两个表位都是来自HLA-A2（+）1型糖尿病患者的循环效应CD 8（+）T细胞的主要靶点。此外，克隆的前胰岛素原信号肽特异性CD 8（+）T细胞在体外杀死人β细胞。重要的是，在高葡萄糖浓度下，前胰岛素原信号表位的β细胞呈递增加，CTL杀伤也增加。这项研究提供了直接证据，表明自身反应性CTL存在于1型糖尿病患者的循环中，并且它们可以杀死人类β细胞。这些结果还确定了自身抗原呈递的机制，该机制处于病理生理学调节下，并且可以在临床糖尿病发展的后期阶段使产生胰岛素的β细胞暴露于增加的细胞毒性。我们的研究结果表明，自身反应性CTL是1型糖尿病免疫干预的重要靶点，并主张早期积极的胰岛素治疗以保护剩余的β细胞。
The final pathway of beta cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill beta cells via recognition of a glucose-regulated epitope. First, we identified 2 naturally processed epitopes from the human preproinsulin signal peptide by elution from HLA-A2 (specifically, the protein encoded by the A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8(+) T cells from HLA-A2(+) patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide-specific CD8(+) T cells killed human beta cells in vitro. Critically, at high glucose concentration, beta cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human beta cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing beta cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining beta cells.