| Autor: |
Mengjun Zhang, Yuanqiang Wang, Xiangqian Li, Gang Meng, Xiaoling Chen, Lina Wang, Zhihua Lin, Li Wang |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Frontiers in Immunology, Vol 12 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
1664-3224 |
| DOI: |
10.3389/fimmu.2021.713276 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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