IFN regulatory factor-2 deficiency revealed a novel checkpoint critical for the generation of peripheral NK cells
IFN regulatory factor-2 deficiency revealed a novel checkpoint critical for the generation of peripheral NK cells
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DOI：
10.4049/jimmunol.174.10.6005
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发表时间：
2005-05-15
影响因子：
4.4
通讯作者：
Hida, S
中科院分区：
文献类型：
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作者：
Taki, S;Nakajima, S;Hida, S
尽管NK细胞在先天免疫中起着至关重要的作用，但与T细胞和B细胞相比，人们对NK细胞的发育知之甚少。已知缺乏转录因子IFN调节因子-2 （IRF-2）的小鼠表现为NK细胞缺乏症。然而，IRF-2在NK细胞发育中的作用尚不清楚。在这项研究中，我们发现irf -2缺陷小鼠的外周NK细胞缺乏是由于成熟NK细胞的选择性丧失，而不是成熟阻滞，这些小鼠的NK细胞表现出非常不成熟的表面表型（CD11b（低）Dx5（低）），NK受体表达高度受损。相比之下，骨髓中irf -2缺陷的NK细胞（BM）表现出相对成熟的表型（CD11b（低）Dx5（高）），NK受体库受损较少。此外，发现irf -2缺陷小鼠的BM NK细胞几乎正常增殖，但凋亡加速。这些观察结果表明，NK细胞的成熟可以推进到BM的晚期，但不是最终阶段，而这些细胞由于缺乏IRF-2的过早死亡而无法参与外周NK细胞池。相比之下，il -15缺失小鼠BM中NK细胞数量和Ly49表达的减少要比IRF-2（-/-）小鼠严重得多。因此，IRF-2（-/-）小鼠的外周和中枢NK细胞缺陷差异揭示了NK细胞成熟的一个新的晚期检查点，不同于早期il -15依赖性扩增阶段。
NK cell development is far less understood compared with that of T and B cells despite the critical importance of NK cells in innate immunity. Mice lacking the transcription factor IFN regulatory factor-2 (IRF-2) are known to exhibit NK cell deficiency. However, the role of IRF-2 in NK cell development has remained unclear. In this study we found that NK cell deficiency in the periphery in IRF-2-deficient mice was due to selective loss of mature NK cells, but not to maturation arrest, and NK cells in these mice exhibited very immature surface phenotypes (CD11b(low)Dx5(low)) with highly compromised NK receptor expression. In contrast, IRF-2-deficient NK cells in bone marrow (BM) showed relatively mature phenotypes (CD11b(low)Dx5(high)) with less compromised NK receptor repertoire. Furthermore, BM NK cells in IRF-2-deficient mice were found to proliferate almost normally, but underwent accelerated apoptosis. These observations indicated that NK cell maturation could advance up to a late, but not the final, stage in the BM, whereas these cells were incapable of contributing to the peripheral NK cell pool due to premature death in the absence of IRF-2. In contrast, NK cell numbers and Ly49 expression were much more severely reduced in BM in IL-15-deficient mice than in IRF-2(-/-) mice. The differential peripheral and central NK cell deficiencies in IRF-2(-/-) mice thus revealed a novel late checkpoint for NK cell maturation, distinct from the early IL-15-dependent expansion stage.