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CD39划分了具有明显细胞毒性和对人类小岛的调节功能的化学抗原受体调节性T细胞子集

Xiangni Wu^1,2, Pin-I Chen¹, Robert L Whitener³

¹Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States.

Frontiers in immunology

|July 15, 2024

概括

化学抗原受体 (CAR) 针对1型糖尿病 (T1D) 的T细胞表现出可变的细胞毒性. 在CAR T细胞上的CD39表达影响了它们的杀伤能力,CD39阳性细胞在免疫治疗中更安全.

科学领域:

免疫学免疫学免疫学
细胞生物学细胞生物学
自免疫性疾病自免疫性疾病

背景情况:

人类调节性T细胞 (Tregs) 对免疫抑制至关重要,它们的功能障碍与1型糖尿病 (T1D) 等自身免疫性疾病有关.
化学抗原受体 (CAR) 工程Tregs通过向胰腺小岛为T1D提供了潜在的治疗策略.
了解Treg子集功能对于优化CAR T细胞治疗至关重要.

研究的目的:

评估CAR向人类Tregs对人类单细胞和小岛贝塔细胞的疗效和安全性.
研究CD39表达在调节CAR Treg细胞毒性的作用.
探索PD-1/PD-L1通路对CAR Treg与β细胞相互作用的影响.

主要方法:

在体外共同培养实验中,使用HLA-A2-CAR (A2-CAR) 工程Tregs与人类单细胞,β细胞系和初级人类岛屿β细胞进行了实验.
在CAR Treg亚组中分析CD39表达水平和与细胞毒性的相关性.
在孤立的CD39-阳性和CD39-阴性CAR Treg子集中评估大酶B的表达.
对β细胞PD-L1和PD-L2表达的研究以及PD-1/PD-L1通路阻塞对细胞死亡的影响.

主要成果:

A2-CAR Tregs表现出二分类细胞毒性,杀死单细胞和岛屿β细胞.
在CAR Tregs上CD39表达分离了它们的细胞毒性活性,CD39低/负Tregs表现出更高的细胞毒性.
与CD39阳性CAR Tregs相比,单独的CD39阴性CAR Tregs显示了较高的花粉酶B表达和细胞毒性.
在对A2-CAR Tregs的反应中,β细胞上调了PD-L1和PD-L2,PD-1/PD-L1通路阻塞增强了β细胞死亡.

结论:

汽车工程可以强调Treg子集内固有的生物学差异.
CD39表达是CAR Treg安全性和有效性的关键决定因素.
CD39阳性Tregs是CAR Treg疗法更安全的选择,旨在诱导胰腺小岛等组织的耐受性.
在CAR Treg免疫疗法期间,PD-1/PD-L1通路对β细胞起着保护作用.

关键词:

在Treg-regulatory T细胞中,T细胞是最重要的.仿制性抗原受体的仿制性抗原受体细胞毒性细胞毒性免疫调节免疫调节第1类糖尿病 1型糖尿病

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