Single-cell transcriptomics Transplant tolerance CD4+ regulatory T cells PD-1 Human pancreatic beta cells
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摘要

Abstract Background We have previously reported an antigen-specific protocol to induce transplant tolerance and linked suppression to human embryonic stem cell (hESC)-derived tissues in immunocompetent mice through coreceptor and costimulation blockade. However, the exact mechanisms of acquired immune tolerance in this model have remained unclear. Methods We utilize the NOD.Foxp3 hCD2 reporter mouse line and an ablative anti-hCD2 antibody to ask if CD4+FOXP3+ regulatory T cells (Treg) are required for coreceptor and costimulation blockade-induced immune tolerance. We also perform genome-wide single-cell RNA-sequencing to interrogate Treg during immune rejection and tolerance and to indicate possible mechanisms involved in sustaining Treg function. Results We show that Treg are indispensable for tolerance induced by coreceptor and costimulation blockade as depletion of which with an anti-hCD2 antibody resulted in rejection of hESC-derived pancreatic islets in NOD.Foxp3 hCD2 mice. Single-cell transcriptomic profiling of 12,964 intragraft CD4+ T cells derived from rejecting and tolerated grafts reveals that Treg are heterogeneous and functionally distinct in the two outcomes of transplant rejection and tolerance. Treg appear to mainly promote chemotactic and ubiquitin-dependent protein catabolism during transplant rejection while seeming to harness proliferative and immunosuppressive function during tolerance. We also demonstrate that this form of acquired transplant tolerance is associated with increased proliferation and PD-1 expression by Treg. Blocking PD-1 signaling with a neutralizing anti-PD-1 antibody leads to reduced Treg proliferation and graft rejection. Conclusions Our results suggest that short-term coreceptor and costimulation blockade mediates immune tolerance to hESC-derived pancreatic islets by promoting Treg proliferation through engagement of PD-1. Our findings could give new insights into clinical development of hESC-derived pancreatic tissues, combined with immunotherapies that expand intragraft Treg, as a potentially sustainable alternative treatment for T1D.

译文

背景: 我们之前已经报道了一种抗原特异性方案,通过共受体和共刺激阻断,在免疫活性小鼠中诱导移植耐受和与人类胚胎干细胞 (hESC) 来源的组织相关的抑制。然而,该模型中获得性免疫耐受的确切机制仍不清楚。方法我们利用 NOD.Foxp3 hCD2 报告鼠系和一种消融性 anti-hCD2 抗体来询问 CD4 FOXP3 调节性 T 细胞 (regulatory T cells,Treg) 是否是辅助受体和共刺激阻滞诱导的免疫耐受所必需的。我们还进行全基因组单细胞 RNA 测序,以在免疫排斥和耐受期间询问 Treg,并指示参与维持 Treg 功能的可能机制。结果我们表明,在共受体和共刺激阻滞诱导的耐受中,调节性 t 细胞是不可或缺的,因为用 anti-hCD2 抗体耗尽后会导致 NOD.Foxp3 hCD2 小鼠的 hESC 衍生胰岛排斥反应。来自排斥和耐受移植物的 12,964 个受体内 CD4 T 细胞的单细胞转录组学分析表明,在移植排斥和耐受的两种结果中,调节性 T 细胞是异质性和功能不同的。在移植排斥反应中,Treg 似乎主要促进趋化和泛素依赖性蛋白分解代谢,同时似乎在耐受期间利用增殖和免疫抑制功能。我们还证明了这种形式的获得性移植耐受与调节性 t 细胞的增殖和 PD-1 表达增加有关。用中和性 PD-1 抗体阻断 anti-PD-1 信号通路,可减少 Treg 增殖和移植物排斥反应。结论我们的结果表明,短期的共刺激受体和共刺激阻断通过 PD-1 的参与促进调节性 t 细胞的增殖,从而介导对 hESC 来源的胰岛的免疫耐受。我们的发现可以为 hESC 来源的胰腺组织的临床发展提供新的见解,结合免疫疗法,扩大 agraft 内的 Treg,作为 T1D 的一种潜在的可持续替代治疗。

regulatory T cells

肿瘤 Tregs 临床研究术语
概述  :  

名为Tregs(The regulatory T cells)的调节性T细胞是种天然存在的T细胞亚群,它们能够负向调节机体免疫反应,通过诱导和维持对自身抗原的耐受性来维持体内免疫平衡。在健康人体内,Tregs能抑制过度的免疫反应,从而预防自身免疫性疾病。但另一方面,它们也可能会限制免疫系统对抗癌症的能力,让肿瘤细胞逃避免疫监视。 分类调节性T细胞可以分为天然产生的自然调节性T细胞,主要是CD4+CD25+Treg;诱导产生的适应性调节性T细胞,它是小剂量抗原或免疫抑制性细胞因子诱导

Regulatory   /ˈrɛɡjʊˌleɪtɔri/

释    义   adj. 管理的;控制的;调整的

同根词   regulation adj. 规定的;平常的;regulative adj. 调整的,调节的;管制的;regulation n. 管理;规则;校准;regulator n. 调整者;校准器;regularization n. 规则化;调整;合法化;

例    句   Perhaps the best reason for regulators to be suspicious about innovation is that so much of it in the modern world is aimed at facilitating regulatory and tax arbitrage. 监管者之所以对创新怀有疑虑,最关键的原因可能在于,现代社会中太多创新的目的都是为监管和税收套利提供便利。

 

Cells 

释    义   n. [细胞] 细胞;单元格(cell的复数);牢房;小屋;v. 住在牢房中(cell的三单形式)

例    句   If you try to shift cells up and down, then when you unhide the hidden cells, where should everything shift? 如果您尝试改变单元格的向上和向下,然后当你打开隐藏的单元格,所有内容应该在哪里移动?

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