Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP
Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP
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DOI：
10.1182/blood-2005-03-1337
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发表时间：
2006-02-01
期刊：
影响因子：
20.3
通讯作者：
Nakakuma, H
中科院分区：
文献类型：
--
作者：
Hanaoka, N;Kawaguchi, T;Nakakuma, H
阵发性睡眠性血红蛋白尿(PNH)克隆扩增的机制尚不清楚。PNH克隆含有PIGA突变，不合成糖基磷脂酰肌醇(GPI)，导致GPI连接的膜蛋白缺失。在再生障碍性贫血患者中，GPI缺陷的血细胞通常在遭受细胞毒细胞诱导的免疫介导的骨髓损伤时扩张，因此表明这种损伤允许PNH克隆选择性地扩张。我们以前报道过，当白血病K562细胞获得PIGA突变时，它们在体外优先存活于自然杀伤(NK)细胞介导的细胞毒作用。我们在这里表明，存活归因于缺乏应激诱导的GPI连接的膜蛋白ULBP1和ULBP2，它们激活NK和T细胞。在表达GPI的K562细胞上检测到ULBP，而在GPI缺陷的K562细胞上检测不到ULBP。在NK细胞上存在针对ULBPs或其受体NKG2D的抗体时，表达GPI的细胞对NK的敏感性与GPI缺陷的细胞一样低。因此，NK细胞在体外没有ULBP缺陷的细胞。仅在部分PNH患者的GPI表达的血细胞上发现ULBP，而在健康人中没有发现。患者的粒细胞部分被自体细胞毒细胞杀死，这意味着ULBP相关的血细胞损伤。在这种情况下，缺乏ULBP可能允许对PNH克隆进行免疫选择。
The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-Iinked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-Iinked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. In the presence of antibodies to either the ULBPs or their receptor NKG2D on NK cells, GPI-expressing cells were as less NK sensitive as GPI-deficient cells. NK cells therefore spared ULBP-deficient cells in vitro. The ULBPs were identified only on GPI-expressing blood cells of a proportion of patients with PNH but none of healthy individuals. Granulocytes of the patients partly underwent killing by autologous cytotoxic cells, implying ULBP-associated blood cell injury. In this setting, the lack of ULBPs may allow immunoselection of PNH clones.