STRUCTURE OF TCR ON TLYMPHOCYTES HARNESSING GRAFT-VERSUS-LEUKEMIA EFFECT

我们已经发现异基因造血干细胞移植物的受体在移植后具有αβ TCR库的偏斜，这是供体来源的成熟T淋巴细胞增殖的结果，这些成熟T淋巴细胞可以在受体中存活数年。当移植后发生CMV相关疾病时，在CMV血清阳性受者中观察到来自巨细胞病毒（CMV）血清阳性骨髓供体的供体源性TCRαβ+ T克隆群体的扩增。这些结果表明，异基因造血干细胞移植（HSCT）后外周血中TCRαβ+ T细胞的克隆性扩增和导致的偏斜αβ TCR库主要反映了对微生物的反应。我们还发现，人allo-HSCT后，Vδ1+ _YδT淋巴细胞的稳定克隆性扩增持续数年。CDR 3大小谱分析显示，42例患者中有23例具有高度偏斜的Vδ1+ T细胞TCR谱系。Vδ1+ TCR的寡克隆性与GVHD和白血病复发等临床结局无明显相关性。在检查的17名患者中的8名中，在克隆扩增的Vδ1+ T细胞的TCR的CDR 3区中观察到-WGI-氨基酸序列。在4例患者中观察到-YWG-序列。所有接受检查的受者均为EBV-VCA IgG和EBNA血清学阳性。自体EBV转化的B细胞可诱导Vδ1+ T细胞扩增。在用自体EBV-LCL刺激后，Vδ1+ TCR的CDR 3大小分布模式变得偏斜，并且具有-LEEYWGLPH-CDR 3序列的T细胞克隆在用自体EBV-LCL的培养物中占优势。这些结果表明，CDR 3结构可能有助于Vδ1+ T细胞识别EBV相关抗原。allo-HSCT后Vδ1+ TCR的偏斜可能是对人类中广泛存在的感染性抗原如EBV的应答的结果。

We have found that recipients of allogeneic hematopoietic stem cell grafts have a skewing of the αβ TCR repertoire after transplant and this is a result of the proliferation of donor-derived mature T lymphocytes which can survive in recipients for several years. Expansion of the population of donor-derived TCRαβ+ T clones from a cytomegalovirus (CMV)-seropositive bone marrow donor was observed in a CMV-seropositive recipient when developing CMV-associated disease after transplantation. These results suggest that the clonal expansion of TCRαβ+ T cells and resulting skewed αβ TCR repertoire in peripheral blood following allogeneic hematopoietic stem cell transplantation (HSCT) primarily reflect the response to microorganisms. We have also found that stable clonal expansion of Vδ1+ _YδT lymphocytes persisted for several years after human allo-HSCT. CDR3 size spectratyping analysis revealed that twenty-three out of forty-two patients had highly skewed TCR repertoires of the Vδ1+ T cells. There was no apparent association between the oligoclonality of Vδ1+ TCRs and clinical outcome such as GVHD and leukemia relapse. In eight out of seventeen patients examined, the -WGI-amino acid sequence was observed in the CDR3 region of TCRs of clonally expanded Vδ1+ T cells. The -YWG-sequence was observed in four patients. All recipients examined were serologically positive for EBV-VCA IgG and EBNA. Autologous EBV transformed B cells could induce the expansion of Vδ1+ T cells. The CDR3 size distribution patterns of Vδ1+ TCRs became skewed after stimulation with autologous EBV-LCL, and the T cell clone with the -LEEYWGLPH-CDR3 sequence predominated in the culture with autologous EBV-LCL. These results suggest the CDR3 structure may contribute to recognition of EBV-associated antigens by Vδ1+ T cells. Skewing of the Vδ1+ TCR after allo-HSCT may be the result of the response to infectious antigens widely existing in humans such as EBV.