A Single L/D-Substitution at Q4 of the mInsA(2-10) Epitope Prevents Type 1 Diabetes in Humanized NOD Mice.
A Single L/D-Substitution at Q4 of the mInsA(2-10) Epitope Prevents Type 1 Diabetes in Humanized NOD Mice.
复制标题
mInsA(2-10) 表位 Q4 处的单个 L/D 取代可预防人源化 NOD 小鼠中的 1 型糖尿病
DOI：
10.3389/fimmu.2021.713276
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Zhang M;Wang Y;Li X;Meng G;Chen X;Wang L;Lin Z;Wang L
自身反应性CD 8 + T细胞在胰岛β细胞的破坏和1型糖尿病（T1 D）的发生中起着不可或缺的关键作用。胰岛素是T1 D中的必需β细胞自身抗原。胰岛素A链的HLA-A*0201限制性表位（mInsA 2 -10）是NOD.β2mnull.HHD小鼠中自身反应性CD 8 + T细胞的免疫显性配体。在表位内的T细胞受体（TCR）接触位置处携带氨基酸取代的改变的肽配体（APLs）有可能通过触发改变的TCR信号传导来调节自身免疫应答。在这里，我们使用分子模拟策略来指导APL候选物的产生，通过在mInsA 2 -10的潜在TCR接触残基（位置4和6）处用D-氨基酸取代L-氨基酸，分别命名为mInsA 2 - 10 DQ 4和mInsA 2 - 10 DC 6。我们发现，给予mInsA 2 - 10 DQ 4而不是DC 6显著抑制了NOD.β2mnull.HHD小鼠中T1 D的发展。从机制上讲，mInsA 2 - 10 DQ 4治疗不仅显著消除了mInsA 2 -10自身反应性CD 8 + T细胞应答，而且还防止了NOD.β2mnull.HHD小鼠胰腺中CD 4 + T和CD 8 + T细胞的浸润以及炎症应答。本研究为APL疫苗的开发提供了新的策略。
Autoreactive CD8+ T cells play an indispensable key role in the destruction of pancreatic islet β-cells and the initiation of type 1 diabetes (T1D). Insulin is an essential β-cell autoantigen in T1D. An HLA-A*0201-restricted epitope of insulin A chain (mInsA2-10) is an immunodominant ligand for autoreactive CD8+ T cells in NOD.β2mnull.HHD mice. Altered peptide ligands (APLs) carrying amino acid substitutions at T cell receptor (TCR) contact positions within an epitope are potential to modulate autoimmune responses via triggering altered TCR signaling. Here, we used a molecular simulation strategy to guide the generation of APL candidates by substitution of L-amino acids with D-amino acids at potential TCR contact residues (positions 4 and 6) of mInsA2-10, named mInsA2-10DQ4 and mInsA2-10DC6, respectively. We found that administration of mInsA2-10DQ4, but not DC6, significantly suppressed the development of T1D in NOD.β2mnull.HHD mice. Mechanistically, treatment with mInsA2-10DQ4 not only notably eliminated mInsA2-10 autoreactive CD8+ T cell responses but also prevented the infiltration of CD4+ T and CD8+ T cells, as well as the inflammatory responses in the pancreas of NOD.β2mnull.HHD mice. This study provides a new strategy for the development of APL vaccines for T1D prevention.