Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic beta cells that produce insulin. The latest advances in stem cell (SC)-beta cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC-beta cells. A promising strategy to overcome immune rejection is to genetically engineer SC-beta cells. We previously identified Renalase (Rnls) as a novel target for beta cell protection. Here we show that Rnls deletion endows beta cells with the capacity to modulate the metabolism and function of immune cells within the local graft microenvironment. We used flow cytometry and single-cell RNA sequencing to characterize beta cell graft-infiltrating immune cells in a mouse model for T1D. Loss of Rnls within transplanted beta cells affected both the composition and the transcriptional profile of infiltrating immune cells in favor of an anti-inflammatory profile with decreased antigen presenting capacity. We propose that changes in beta cell metabolism mediate local immune regulation and that this feature could be exploited for therapeutic goals.

中文翻译：

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β细胞中的保护性肾酶缺陷影响自身免疫性糖尿病的免疫代谢和功能


1 型糖尿病 (T1D) 是由免疫介导的产生胰岛素的胰腺 β 细胞丢失引起的。干细胞 (SC)-β 细胞分化方法的最新进展使得 T1D 的细胞替代疗法变得可行。然而，反复出现的自身免疫会迅速破坏移植的 SC-β 细胞。克服免疫排斥的一个有前景的策略是对 SC-β 细胞进行基因改造。我们之前将肾酶 (Rnls) 确定为 β 细胞保护的新靶点。在这里，我们证明 Rnls 缺失赋予 β 细胞调节局部移植物微环境中免疫细胞的代谢和功能的能力。我们使用流式细胞术和单细胞 RNA 测序来表征 T1D 小鼠模型中的 β 细胞移植物浸润免疫细胞。移植的β细胞内Rnls的丢失影响了浸润免疫细胞的组成和转录谱，有利于抗炎谱，同时降低了抗原呈递能力。我们认为β细胞代谢的变化介导局部免疫调节，并且可以利用这一特征来实现治疗目标。