Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
PLoS Pathog. 2022 Apr 22;18(4):e1010206. doi: 10.1371/journal.ppat.1010206. eCollection 2022 Apr.
Reconstitution of the T cell repertoire after allogeneic stem cell transplantation is a long and often incomplete process. As a result, reactivation of Epstein-Barr virus (EBV) is a frequent complication that may be treated by adoptive transfer of donor-derived EBV-specific T cells. We generated donor-derived EBV-specific T cells by stimulation with peptides representing defined epitopes covering multiple HLA restrictions. T cells were adoptively transferred to a patient who had developed persisting high titers of EBV after allogeneic stem cell transplantation for angioimmunoblastic T-cell lymphoma (AITL). T cell receptor beta (TCRβ) deep sequencing showed that the T cell repertoire of the patient early after transplantation (day 60) was strongly reduced and only very low numbers of EBV-specific T cells were detectable. Manufacturing and in vitro expansion of donor-derived EBV-specific T cells resulted in enrichment of EBV epitope-specific, HLA-restricted T cells. Monitoring of T cell clonotypes at a molecular level after adoptive transfer revealed that the dominant TCR sequences from peptide-stimulated T cells persisted long-term and established an EBV-specific TCR clonotype repertoire in the host, with many of the EBV-specific TCRs present in the donor. This reconstituted repertoire was associated with immunological control of EBV and with lack of further AITL relapse.
异基因干细胞移植后 T 细胞受体库的重建是一个漫长且常常不完全的过程。因此，EB 病毒（Epstein-Barr virus，EBV）的再激活是一种常见的并发症，可以通过输注供者来源的 EBV 特异性 T 细胞进行治疗。我们通过用代表多个 HLA 限制的多个 EBV 表位的肽段刺激来产生供者来源的 EBV 特异性 T 细胞。我们将这些 T 细胞过继转移到一位患有血管免疫母细胞性 T 细胞淋巴瘤（angioimmunoblastic T-cell lymphoma，AITL）的患者，该患者在接受异基因干细胞移植后持续出现高滴度 EBV。T 细胞受体β（T cell receptor beta，TCRβ）深度测序显示，患者在移植后早期（第 60 天）的 T 细胞受体库明显减少，只能检测到非常少量的 EBV 特异性 T 细胞。供者来源的 EBV 特异性 T 细胞的制造和体外扩增导致 EBV 表位特异性、HLA 限制性 T 细胞的富集。在过继转移后对 T 细胞克隆型进行分子水平监测显示，来自肽刺激的 T 细胞的优势 TCR 序列长期存在，并在宿主中建立了 EBV 特异性 TCR 克隆型库，其中许多 EBV 特异性 TCR 存在于供者中。这种重建的库与 EBV 的免疫控制以及缺乏进一步的 AITL 复发有关。
