Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, De Coene C, Selz F, Le Deist F, Fischer A
Institut National de la Santé et de la Recherche Médicale U 429, Hôpital Necker-Enfants Malades, Paris, France.
Blood. 1996 Nov 15;88(10):3901-9.
Natural killer (NK) cells are characterized by their ability to mediate spontaneous cytotoxicity against susceptible tumor cells and infected cells. They differentiate from hematopoietic progenitor cells. Patients with X-linked severe combined immunodeficiency (SCID X1) carry mutations in the gamma c cytokine receptor gene that result in lack of both T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, and IL-15 cytokines, which share gamma c receptor subunit, in NK cell differentiation, we have studied NK cell differentiation from cord blood CD34 (+) cells in the presence of either stem cell factor (SCF), IL-2, and IL-7 or SCF and IL-15. The former cytokine combination efficiently induced CD34 (+) CD7 (+) cord blood cells to proliferate and mature into NK cells, while the latter was also able to induce NK cell differentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK cells expressed CD56 and efficiently killed K562 target cells. These results show that IL-15 could play an important role in the maturation of NK cell from cord blood progenitors. Following retroviral-mediated gene transfer of gamma c into SCID X1 bone marrow progenitors, it was possible to reproduce a similar pattern of NK cell differentiation in two SCID-X1 patients with SCF + IL-2 + IL-7 and more efficiently in one of them with SCF + IL-15. These results strongly suggest that the gamma c chain transduces major signal(s) involved in NK cell differentiation from hematopoietic progenitor cells and that IL-15 interaction with gamma c is involved in this process at an earlier step than IL-2/IL-7 interactions of gamma c are. It also shows that gene transfer into hematopoietic progenitor cells could potentially restore NK cell differentiation in SCID X1 patients.
自然杀伤（NK）细胞的特点是能够介导针对易感肿瘤细胞和受感染细胞的自发细胞毒性。它们从造血祖细胞分化而来。患有X连锁严重联合免疫缺陷（SCID X1）的患者在γc细胞因子受体基因中携带突变，导致T细胞和NK细胞均缺乏。为了评估共享γc受体亚基的白细胞介素-2（IL-2）、IL-7和IL-15细胞因子在NK细胞分化中的作用，我们研究了在存在干细胞因子（SCF）、IL-2和IL-7或SCF和IL-15的情况下，脐血CD34(+)细胞向NK细胞的分化。前一种细胞因子组合有效地诱导CD34(+)CD7(+)脐血细胞增殖并成熟为NK细胞，而后一种组合也能够诱导更不成熟的CD34(+)CD7(-)脐血细胞分化为NK细胞。NK细胞表达CD56并能有效杀伤K562靶细胞。这些结果表明，IL-15可能在脐血祖细胞向NK细胞的成熟过程中发挥重要作用。在将γc通过逆转录病毒介导的基因转移到SCID X1骨髓祖细胞后，两名SCID-X1患者在使用SCF + IL-2 + IL-7时能够重现类似的NK细胞分化模式，其中一名患者使用SCF + IL-15时效率更高。这些结果强烈表明，γc链转导了参与造血祖细胞向NK细胞分化的主要信号，并且IL-15与γc的相互作用在这一过程中比γc与IL-2/IL-7的相互作用更早参与。这也表明将基因转移到造血祖细胞中可能潜在地恢复SCID X1患者的NK细胞分化。
