具有多样化的人类T细胞受体谱的小鼠在多个HLAI类分子上被选择
Arunraj Dhamodaran1,2,3, Xiaojing Chen1, Niklas Fellmer2
1Molecular Immunology and Gene Therapy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
Nature communications
|July 2, 2025
概括
新的ABab-I小鼠表达了多个人类白细胞抗原I类基因,增强了用于癌症免疫治疗的T细胞受体发现. 这些小鼠提供更广泛的HLA覆盖范围,可能扩大患者对T细胞受体治疗的资格.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 基因治疗 基因治疗
背景情况:
- T细胞受体 (TCR) 基因疗法在癌症治疗方面表现有前途.
- 具有最佳狂热度的人类TCR是治疗的理想选择,最好是来自不耐受宿主.
- 上一篇ABab-A2小鼠表达人类TCR位点和单个HLA-A*02:01基因.
研究的目的:
- 开发一种具有更广泛的人类白细胞抗原I类 (HLA-I) 覆盖范围的小鼠模型,以加强TCR发现.
- 评估多HLA-I表达对T细胞谱和免疫反应的影响.
- 为了促进同时发现表位和TCR,以便在TCR-T细胞治疗中得到更广泛的应用.
主要方法:
- 通过将多个HLA-I基因 (HLA-A*03:01, -A*11:01, -B*07:02, -B*15:01, -C*04:01, -C*07:02) 引入到使用PiggyBac转位子的ABab-A2小鼠中来产生ABab-I小鼠.
- 在ABab-I和ABab-A2小鼠之间对T细胞种群 (CD8+计数,CD8/CD4比率) 和TCR谱系多样性 (V(D) J-TCRß克隆型) 的比较分析.
- 在ABab-I小鼠中对病毒,瘤相关和瘤特异抗原的免疫反应的评估.
主要成果:
- 与ABab-A2小鼠相比,ABab-I小鼠的外围CD8+T细胞数量增加,CD8/CD4比率更高.
- 在ABab-I小鼠中观察到的更独特的V(D) J-TCRß克隆类型的更广泛的TCR谱.
- 多HLA-I表达选择的TCR平均具有较长的互补决定性区域3 (CDR3).
- ABab-I小鼠对各种抗原表现出强大的免疫反应.
结论:
- ABab-I小鼠为发现具有广泛HLA覆盖的T细胞受体 (TCR) 提供了宝贵的平台.
- 这种模型可以加速用于癌症免疫治疗的TCRs的识别,从而可能增加患者接受TCR-T治疗的资格.
- 这些发现支持使用多HLA-I表达小鼠来推进基于TCR的癌症疗法.
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