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对 rhesus macaque TCR 常数区域的修改可以改善 TCR 细胞表面表达
Lori V Coren1, Matthew T Trivett1, Jorden L Welker1
1AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
PloS one
|January 9, 2025
概括
在 rhesus macaque 模型中优化 T 细胞受体 (TCR) 结构可增强表面表达. 恒定区域的化显著增加了TCR表达,这对于细胞免疫治疗的发展至关重要.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞疗法细胞疗法
- 生物技术是生物技术.
背景情况:
- T细胞免疫疗法的有效性依赖于工程细胞上足够的表面抗原受体表达.
- 挑战包括优化工程,编码序列,并防止异源和内源T细胞受体 (TCR) 链的错误配对.
- 临床前模型对于完善工程设计和评估安全至关重要.
研究的目的:
- 为了增强 rhesus macaque T 细胞受体 (TCR) 表面表达在原始细胞中,以改进基于 TCR 的细胞免疫疗法模型.
- 评估五种替代的TCRαβ常数区域结构对它们对表面表达和功能的影响.
主要方法:
- 在 rhesus macaque 主细胞中生成了五个不同的 TCRαβ 常数区域构造SIV Gag 特定的 TCR.
- 构造包括人类编码子优化的 rhesus macaque TCR,二硫化链接,最小的鼠标替代,完全的鼠标化和使用 FG 循环修改的鼠标化.
- 在抗原特异性刺激时评估表面表达水平和细胞因子产量.
主要成果:
- 与野生类型相比,化或对常数区域进行最小氨基酸替换显著增加了 rhesus macaque TCR 表面表达.
- 所有工程TCR构造都保持了其诱导细胞因子产生的能力,以应对相关的抗原刺激.
- 特定的修改,特别是化,在增强表面表达方面被证明是最有效的.
结论:
- 对TCR常数区域的修改,特别是化,是增加 rhesus模型表面TCR表达的有效策略.
- 这些优化的TCR结构保留了抗原特异性功能,支持它们在临床前免疫疗法研究中的使用.
- 这些发现为基于TCR的细胞免疫治疗的先进 rhesus macaque 模型的 TCR 设计提供了信息.
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