Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Biochem Biophys Res Commun. 2021 Jan 1;534:680-686. doi: 10.1016/j.bbrc.2020.11.019. Epub 2020 Nov 15.
Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing β cells. The response of autoreactive T cells to β cell antigens plays a central role in the development of T1D. Recently, fusion peptides composed by insulin C-peptide fragments and other proteins were reported as β cell target antigens for diabetogenic CD4 T cells in non-obese diabetic (NOD) mice. In this study, we generated a T cell-receptor (TCR)-like monoclonal antibody (mAb) against a fusion peptide bound to major histocompatibility complex (MHC) class II component to elucidate the function of the fusion peptides in T1D. In addition, we developed a novel NFAT-GFP TCR reporter system to evaluate the TCR-like mAb. The NFAT-GFP reporter T cells expressing the diabetogenic TCR were specifically activated by the fusion peptide presented on the MHC class II molecules. By using the NFAT-GFP reporter T cells, we showed that the TCR-like mAb blocks the diabetogenic T cell response against the fusion peptide presented on the MHC class II molecules. Furthermore, the development of T1D was ameliorated when pre-diabetic NOD mice were treated with this mAb. These findings suggest that NFAT-GFP reporter T cells are useful to assess the function of specific TCR and the recognition of fusion peptides by T cells is crucial for the pathogenesis of T1D.
1 型糖尿病（T1D）是一种由胰岛素产生细胞β破坏引起的自身免疫性疾病。自身反应性 T 细胞对β细胞抗原的反应在 T1D 的发展中起核心作用。最近，报告称由胰岛素 C 肽片段和其他蛋白质组成的融合肽是非肥胖型糖尿病（NOD）小鼠中致糖尿病 CD4 T 细胞的β细胞靶抗原。在这项研究中，我们针对与主要组织相容性复合物（MHC）Ⅱ类成分结合的融合肽产生了一种 T 细胞受体（TCR）样单克隆抗体（mAb），以阐明融合肽在 T1D 中的作用。此外，我们开发了一种新型的 NFAT-GFP TCR 报告系统来评估 TCR 样 mAb。表达致糖尿病 TCR 的 NFAT-GFP 报告 T 细胞可被 MHC Ⅱ类分子上呈递的融合肽特异性激活。通过使用 NFAT-GFP 报告 T 细胞，我们表明 TCR 样 mAb 可阻断 MHC Ⅱ类分子上呈递的融合肽对致糖尿病 T 细胞反应的抑制作用。此外，当用这种 mAb 治疗糖尿病前期 NOD 小鼠时，T1D 的发展得到了改善。这些发现表明 NFAT-GFP 报告 T 细胞可用于评估特定 TCR 的功能，并且 T 细胞对融合肽的识别对于 T1D 的发病机制至关重要。
