Department of Hematology, Leiden University Medical Center, Leiden, Netherlands.
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory for Blood Cell Research, Amsterdam, Netherlands.
Front Immunol. 2021 Mar 29;12:630440. doi: 10.3389/fimmu.2021.630440. eCollection 2021.
T-cell products derived from third-party donors are clinically applied, but harbor the risk of off-target toxicity induction of allo-HLA cross-reactivity directed against mismatched alleles. We used third-party donor-derived virus-specific T cells as model to investigate whether virus-specificity, HLA restriction and/or HLA background can predict the risk of allo-HLA cross-reactivity. Virus-specific CD8 T cells were isolated from HLA-A01:01/B08:01 or HLA-A02:01/B07:02 positive donors. Allo-HLA cross-reactivity was tested using an EBV-LCL panel covering 116 allogeneic HLA molecules and confirmed using K562 cells retrovirally transduced with single HLA-class-I alleles of interest. HLA-B08:01-restricted T cells showed the highest frequency and diversity of allo-HLA cross-reactivity, regardless of virus-specificity, which was skewed toward multiple recurrent allogeneic HLA-B molecules. Thymic selection for other HLA-B alleles significantly influenced the level of allo-HLA cross-reactivity mediated by HLA-B08:01-restricted T cells. These results suggest that the degree and specificity of allo-HLA cross-reactivity by T cells follow rules. The risk of off-target toxicity after infusion of incompletely matched third-party donor-derived virus-specific T cells may be reduced by selection of T cells with a specific HLA restriction and background.
从第三方供体获得的 T 细胞产品在临床上得到应用，但存在靶向毒性的风险，可诱导针对错配等位基因的同种异体 HLA 交叉反应。我们使用第三方供体来源的病毒特异性 T 细胞作为模型，研究病毒特异性、HLA 限制和/或 HLA 背景是否可以预测同种异体 HLA 交叉反应的风险。从 HLA-A01:01/B08:01 或 HLA-A02:01/B07:02 阳性供体中分离病毒特异性 CD8 T 细胞。使用涵盖 116 种同种异体 HLA 分子的 EBV-LCL 面板测试同种异体 HLA 交叉反应，并使用 K562 细胞进行逆转录病毒转导感兴趣的单个 HLA-I 类等位基因进行确认。HLA-B08:01 限制性 T 细胞显示出最高频率和多样性的同种异体 HLA 交叉反应，无论病毒特异性如何，均偏向于多种反复出现的同种异体 HLA-B 分子。针对其他 HLA-B 等位基因的胸腺选择显著影响由 HLA-B08:01 限制性 T 细胞介导的同种异体 HLA 交叉反应的水平。这些结果表明，T 细胞的同种异体 HLA 交叉反应的程度和特异性遵循一定的规律。输注不完全匹配的第三方供体来源的病毒特异性 T 细胞后，通过选择具有特定 HLA 限制和背景的 T 细胞，可能会降低靶向毒性的风险。
