Downregulation of HLA class II is associated with relapse after allogeneic stem cell transplantation and alters recognition by antigen-specific T cells
Downregulation of HLA class II is associated with relapse after allogeneic stem cell transplantation and alters recognition by antigen-specific T cells
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DOI：
10.1007/s12185-021-03273-w
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发表时间：
2022-01-17
影响因子：
2.1
通讯作者：
Kiyoi, Hitoshi
中科院分区：
文献类型：
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作者：
Adachi, Yoshitaka;Sakai, Toshiyasu;Kiyoi, Hitoshi
白血病细胞中供者-患者不匹配的HLA等位基因的基因组缺失是异基因造血干细胞移植（HSCT）后复发的主要原因。错配的 HLA 在 HLA I 类中经常作为单个等位基因或整个区域丢失，但在 HLA II 类中则下调。我们假设 T 细胞对 HLA-I 类和 HLA-II 类相关表位的识别能力可能存在差异，因此这种同种异体免疫压力诱导白血病细胞中的 HLA 改变。为了研究这一点，我们用 T 细胞受体转导的 T (TCR-T) 细胞进行了体外实验。 NY-ESO-1 特异性 TCR-T 细胞对 HLA-A*02:01 低表达的 K562 细胞表现出类似的细胞毒活性。然而，我们证明针对低 HLA-DPB1*05:01 表达系的细胞因子产量从 HLA 表达水平逐渐下降，比正常表达细胞低约 2 个对数。我们使用 HSCT 前后分选纯化的白血病细胞，应用新一代测序，发现 HLA-II 类等位基因有几个明显的下调，这表明移植前的表达始终较低。 HLA-II类的显着下调可能导致抗原特异性T细胞的抗原识别能力下降，可能是与HLA-II类下调相关的免疫逃避机制之一。
Genomic deletion of donor-patient-mismatched HLA alleles in leukemic cells is a major cause of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Mismatched HLA is frequently lost as an individual allele or a whole region in HLA-class I, however, it is downregulated in HLA-class II. We hypothesized that there might be a difference in T cell recognition capacity against epitopes associated with HLA-class I and HLA-class II and consequently such allogeneic immune pressure induced HLA alterations in leukemic cells. To investigate this, we conducted in vitro experiments with T cell receptor-transduced T (TCR-T) cells. The cytotoxic activity of NY-ESO-1-specific TCR-T cells exhibited similarly against K562 cells with low HLA-A*02:01 expression. However, we demonstrated that the cytokine production against low HLA-DPB1*05:01 expression line decreased gradually from the HLA expression level approximately 2-log lower than normal expressors. Using sort-purified leukemia cells before and after HSCT, we applied the next-generation sequencing, and revealed that there were several marked downregulations of HLA-class II alleles which demonstrated consistently low expression from pre-transplantation. The marked downregulation of HLA-class II may lead to decreased antigen recognition ability of antigen-specific T cells and may be one of immune evasion mechanism associated with HLA-class II downregulation.