Li Yi, Zhou Lina, Li Yashu, Zhang Jie, Guo Binbin, Meng Gang, Chen Xiaoling, Zheng Qian, Zhang Linlin, Zhang Mengjun, Wang Li
Institute of Immunology PLA, Third Military Medical University, Chongqing 400038, China.
Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Clin Immunol. 2015 Jul;159(1):63-71. doi: 10.1016/j.clim.2015.04.017. Epub 2015 May 6.
ChgA has recently been identified as the autoantigen for diabetogenic CD4(+) T cells in NOD mice and T1D patients. However, autoreactive CD8(+) T-cell responses targeting ChgA haven't been studied yet. Here several HLA-A0201-restricted peptides derived from mChgA and hChgA were selected by an integrated computational prediction approach, followed by an HLA-A0201 binding assay. MChgA10-19 and mChgA(43-52) peptides, which bound well with HLA-A0201 molecule, induced significant proliferation and IFN-γ-releasing of splenocytes from diabetic NOD.β2m(null).HHD mice. Notably, flow cytometry analysis found that mChgA(10-19) and mChgA(43-52) stimulated the production of IFN-γ, perforin, and IL-17 by splenic CD8(+) T cells of diabetic NOD.β2m(null).HHD mice. Furthermore, hChgA(10-19) and hChgA(43-52)-induced IFN-γ releasing by specific CD8(+) T cells were frequently detected in recent-onset HLA-A0201-positive T1D patients. Thus, this study demonstrated that autoreactive CD8(+) T cells targeting ChgA were present in NOD.β2m(null).HHD mice and T1D patients, and might contribute to pathogenesis of T1D through secreting proinflammatory cytokines and cytotoxic molecules.
ChgA最近被确定为非肥胖型糖尿病（NOD）小鼠和1型糖尿病（T1D）患者中致糖尿病性CD4(+) T细胞的自身抗原。然而，针对ChgA的自身反应性CD8(+) T细胞反应尚未得到研究。在这里，通过综合计算预测方法选择了几种源自小鼠ChgA（mChgA）和人ChgA（hChgA）的HLA-A0201限制性肽段，随后进行了HLA-A0201结合试验。与HLA-A0201分子结合良好的mChgA10 - 19和mChgA(43 - 52)肽段，可诱导糖尿病NOD.β2m(null).HHD小鼠脾细胞显著增殖并释放干扰素-γ（IFN-γ）。值得注意的是，流式细胞术分析发现，mChgA(10 - 19)和mChgA(43 - 52)刺激糖尿病NOD.β2m(null).HHD小鼠脾脏CD8(+) T细胞产生IFN-γ、穿孔素和白细胞介素-17（IL-17）。此外，在近期发病的HLA-A0201阳性T1D患者中经常检测到hChgA(10 - 19)和hChgA(43 - 52)诱导特异性CD8(+) T细胞释放IFN-γ。因此，本研究表明，在NOD.β2m(null).HHD小鼠和T1D患者中存在针对ChgA的自身反应性CD8(+) T细胞，它们可能通过分泌促炎细胞因子和细胞毒性分子促进T1D的发病机制。
