1型糖尿病(T1D)是自身反应性T细胞靶向破坏胰岛β细胞的自身免疫性疾病，CD8+T细胞在其发病机制中起重要作用。预实验结果已证实锌转运体8(ZnT8)是T1D致病性CD8+T细胞的靶抗原。作为胰岛自身抗原的ZnT8为何及如何被机体致病性T细胞识别而打破免疫耐受机制？本研究首先通过检测ZnT8抗原特异性CD8+T细胞对内质网应激状态下人胰岛细胞的免疫反应强度，证明ZnT8在功能异常的内质网经翻译后修饰(PTM)激活了致病性T细胞对新抗原表位的识别和靶向攻击；再利用氨基酸测序、分子筛色谱分析等手段进一步分析ZnT8抗原PTM表位肽的分子结构和蛋白多肽聚集情况，探讨ZnT8经PTM改变蛋白构象、暴露隐匿表位肽结构，增强抗原性及与致病性T细胞亲和力的可能机制。本研究从胰岛抗原PTM激活致病性T细胞靶向识别和免疫攻击的新视角为揭示T1D免疫耐受缺陷机制奠定了基础，也为T1D的防治打开了新思路。

Type 1 diabetes (T1D) is an autoimmune disease in which islet β cells are targeted by autoreactive T cells. Many physiological and environmental triggers associated with T1D increase the potential for abnormal folding, aggregation, and post-translational modification (PTM) of proteins. In the context of genetic susceptibility to autoimmunity and failure of peripheral tolerance, the presentation of abnormally-modified proteins (neo-antigens) by antigen presenting cells initiates T cell-mediated pathogenesis in T1D. In this research, we use human islet cells to prove that PTMs of proteins leads islet β cells to the formation of a highly antigenic epitope for diabetic T cells. And then, we analyze the differences between the naturally occurring and PTM form of the epitope at the molecular level, and explore the possible mechanism how peptide fills the T cell receptor binding groove well after PTM. Not only the pathogenesis might be gained, but also novel diagnostic and therapeutic approaches could be developed for type 1 diabetes if protein modifications were shown to play a critical role in the loss of immune tolerance of the disease.