Abstract：
An important factor in the development of type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and galectin-9 (Gal-9), in β-cells. Therefore, modulation of pancreas-infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating new-onset T1D. We genetically engineered macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict islet autoreactive T lymphocytes and protect β-cells from destruction. Intriguingly, overexpression of Gal-9 stimulated macrophage polarization to the M2 phenotype with immunosuppressive attributes. Alternatively, both PD-L1- and Gal-9-presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhered to T cells via the interaction of programmed cell death protein 1/PD-L1 or T-cell immunoglobulin mucin 3/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T-cell apoptosis and splenic regulatory T (Treg) cell formation in vitro. Notably, PD-L1-Gal-9 aEVs efficaciously reversed new-onset hyperglycemia in NOD mice, prevented T1D progression, and decreased the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas, which together contributed to the preservation of residual β-cell survival and mitigation of hyperglycemia.
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摘要：
1型糖尿病（T1D）发展的一个重要因素是抑制性免疫检查点配体的缺乏，特异性程序性细胞死亡配体1（PD-L1）和半乳糖凝集素-9（Gal-9），在β细胞中。因此，外源性PD-L1或Gal-9对胰腺浸润T淋巴细胞的调节是治疗新发T1D的理想方法。在这里，我们对巨噬细胞进行基因工程改造,生成过表达PD-L1和Gal-9的人工细胞外囊泡(aEVs),这可以限制胰岛自身反应性T淋巴细胞并保护β细胞免受破坏.有趣的是，过表达Gal-9刺激巨噬细胞极化为具有免疫抑制属性的M2表型。或者，PD-L1和Gal-9呈递aEV(PD-L1-Gal-9aEV)均通过程序性细胞死亡蛋白1(PD-1)/PD-L1或T细胞免疫球蛋白粘蛋白3(TIM-3)/Gal-9的相互作用有利地粘附于T细胞.此外，PD-L1-Gal-9aEV在体外显着促进效应T细胞凋亡和脾调节性T细胞（Treg）细胞分化。实际上,PD-L1-Gal-9aEV有效逆转了NOD小鼠的新发高血糖，阻止T1D进展，浸润胰腺的CD4+和CD8+T细胞的比例和活化显著下降，它们共同有助于保留残留的β细胞存活和减轻高血糖。
