Immunobiology -: TCRγδ cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells
Immunobiology -: TCRγδ cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells
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DOI：
10.1038/sj.bmt.1703043
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发表时间：
2001-05-01
影响因子：
4.8
通讯作者：
van de Wiel-van Kemenade, E
中科院分区：
文献类型：
--
作者：
Dolstra, H;Fredrix, H;van de Wiel-van Kemenade, E
细胞毒性T淋巴细胞（CTL）被认为在移植物抗白血病（GVL）反应中起重要作用。不幸的是，GVL反应性通常与危及生命的移植物抗宿主病（GVHD）相关，选择性攻击白血病细胞而不是正常细胞的CTL的特征可能导致开发将GVL与GVHD分开的辅助免疫疗法。（V β 9/V δ 1）CTL，分离自干细胞移植（SCT）后AML患者的外周血，非常有效地裂解新鲜分离的急性髓性白血病（AML）细胞和AML细胞系。有趣的是，HLA匹配的非恶性造血细胞没有被杀死。我们揭示了对第2组HLA-C分子特异的杀伤细胞抑制受体（KIR）p58.2（CD 158 b）负调节这些TCR γ δ CTL所显示的细胞毒性效应子功能。首先，抗HLA-C的抗体增强非恶性细胞的溶解。其次，将HLA-Cw*0304稳定转染到I类阴性细胞系721.221中抑制了裂解。最后，通过固定在表达Fc γ R的鼠P815细胞上的抗体接合p58.2抑制了CD 3和TCR γ δ定向的裂解。与非恶性造血细胞相比，AML细胞表达低得多的水平的MHC I类分子，使得它们易于被p58.2（+）TCR γ δ CTL裂解，这种KIR调节的CTL反应性可能在GVL应答中起作用，而不影响宿主的正常组织并导致GVHD。
Cytotoxic T lymphocytes (CTL) are thought to play an important role in the graft-versus-leukemia (GVL) response. Unfortunately, GVL reactivity is often associated with life-threatening graft-versus-host disease (GVHD), Characterization of CTL that selectively attack leukemic cells but not normal cells may lead to the development of adjuvant immunotherapy that separates GVL from GVHD, Here, we describe TCP gamma delta (V beta9/V delta1) CTL, isolated from the peripheral blood of an AML patient after stem cell transplantation (SCT), that very efficiently lysed freshly isolated acute myeloid leukemia (AML) cells and AML cell lines. Interestingly, HLA-matched non-malignant hematopoietic cells were not killed. We revealed that the killer cell-inhibitory receptor (KIR) p58.2 (CD158b) specific for group 2 HLA-C molecules negatively regulates the cytotoxic effector function displayed by these TCR gamma delta CTL, First, an antibody against HLA-C enhances lysis of nonmalignant cells. Secondly, stable transfection of HLA-Cw*0304 into the class I-negative cell line 721.221 inhibited lysis, Finally, engagement of p58.2 by antibodies immobilized on Fc gammaR-expressing murine P815 cells inhibits CD3- and TCR gamma delta -directed lysis, Compared to non-malignant hematopoietic cells, AML cells express much lower levels of MHC class I molecules making them susceptible to lysis by p58.2(+) TCR gamma delta CTL, Such KIR-regulated CTL reactivity may have a role in the GVL response without affecting normal tissues of the host and leading to GVHD.