异基因骨髓移植后 T 细胞受体库的演变:组织学视角。
T Cell Repertoire Evolution after Allogeneic Bone Marrow Transplantation: An Organizational Perspective.
机构信息
Bone Marrow Transplant Program, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
出版信息
Biol Blood Marrow Transplant. 2019 May;25(5):868-882. doi: 10.1016/j.bbmt.2019.01.021. Epub 2019 Jan 21.
High-throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire, which makes it difficult to correlate T cell reconstitution with clinical outcomes. The associations identified thus far are of a broadly statistical nature, precluding precise modeling of outcomes based on T cell repertoire development following bone marrow transplantation (BMT). Previous work has demonstrated an inherent, mathematically definable order observed in the T cells from a diverse group of donors, which is perturbed in recipients following BMT. In this study, T cell receptor (TCR)-β sequences from HLA-matched related donor and recipient pairs are analyzed to further develop this methodology. TCR-β sequencing from unsorted and sorted T cell subsets isolated from the peripheral blood samples of BMT donors and recipients show conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR-β VJ segment translational symmetry is preserved post-transplantation and even in cases of acute graft-versus-host disease (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antigens. The complexity of the repertoire is significantly diminished after BMT, and the T cell clonal hierarchy is altered post-transplantation. Low-frequency donor clones tended to take on a higher rank in the recipients following BMT, especially in patients with aGVHD. Over time, the repertoire evolves to a more donor-like state in the recipients who did not develop GVHD as opposed to those who did. The results presented here support new methods of quantifying and characterizing post-transplantation T cell repertoire reconstitution.
高通量测序(HTS)人类 T 细胞受体揭示了 T 细胞库的高度复杂性,这使得将 T 细胞重建与临床结果相关联变得困难。迄今为止确定的关联具有广泛的统计性质,排除了基于骨髓移植(BMT)后 T 细胞库发展来精确建模结果的可能性。先前的工作已经证明,在来自不同供体的 T 细胞中观察到一种固有的、数学上可定义的顺序,在 BMT 后受体内这种顺序被打乱。在这项研究中,分析了 HLA 匹配的相关供体和受体对的 T 细胞受体(TCR)-β 序列,以进一步发展这种方法。从 BMT 供体和受体的外周血样本中分离的未分选和分选的 T 细胞亚群的 TCR-β 测序显示,克隆频率中的 VJ 段使用具有保守性和对称性,与 TCR 基因座上基因片段的组织相关。这种 TCR-β VJ 段翻译对称性在移植后得到保留,甚至在急性移植物抗宿主病(aGVHD)的情况下也是如此,这表明 GVHD 的发生代表了供体 T 细胞对受体抗原的多克隆反应。移植后,库的复杂性显著降低,T 细胞克隆层次结构发生改变。低频供体克隆在 BMT 后往往在受体中占据更高的等级,尤其是在发生 aGVHD 的患者中。随着时间的推移,未发生 GVHD的受体内的库演变为更类似于供体的状态,而发生 GVHD 的受体内则不是这样。这里呈现的结果支持了量化和描述移植后 T 细胞库重建的新方法。