A TCR-like antibody against a proinsulin-containing fusion peptide ameliorates type 1 diabetes in NOD mice
A TCR-like antibody against a proinsulin-containing fusion peptide ameliorates type 1 diabetes in NOD mice
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DOI：
10.1016/j.bbrc.2020.11.019
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发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Arase, Hisashi
中科院分区：
文献类型：
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作者：
Matsumoto, Yushi;Kishida, Kazuki;Arase, Hisashi
1型糖尿病(T1D)是一种自身免疫性疾病，由产生胰岛素的β细胞破坏引起。自身反应性T细胞或细胞抗原的应答在T1D的发生发展中起着核心作用。最近，由胰岛素C肽片段和其他蛋白质组成的融合多肽被报道为非肥胖性糖尿病(NOD)小鼠的非肥胖性CD4(+)T细胞的β细胞靶抗原。在这项研究中，我们制备了一种T细胞受体(TCR)样单抗(MAb)，以对抗与主要组织相容性复合体(MHC)II类成分结合的融合肽，以阐明融合肽在T1D中的功能。此外，我们还开发了一种新的NFAT-GFP TCR报告系统来评价TCR样单抗。表达糖尿病原TCR的NFAT-GFP报告T细胞可被MHC-II类分子上的融合肽特异性激活。通过使用NFAT-GFP报告T细胞，我们发现TCR样单抗阻断了针对MHC II类分子上呈现的融合肽的促糖尿病T细胞反应。此外，该单抗对糖尿病前期NOD小鼠的T1D发育也有改善作用。这些结果表明，NFAT-GFP报告T细胞有助于评估特异性TCR的功能，T细胞对融合多肽的识别在T1D的发病机制中起着至关重要的作用。(C)2020 Elsevier Inc.保留所有权利。
Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing beta cells. The response of autoreactive T cells tor, 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 beta 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 prediabetic 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. (C) 2020 Elsevier Inc. All rights reserved.