Baylor College of Medicine, Texas Children's Hospital, 1102 Bates St., FC830.20, Houston, TX 77030, USA.
J Leukoc Biol. 2012 May;91(5):739-50. doi: 10.1189/jlb.0811413. Epub 2012 Feb 17.
The development and survival of NK cells rely on a complex, spatiotemporal gene expression pattern regulated by specific transcription factors in NK cells and tissue-specific microenvironments supported by hematopoietic cells. Here, we show that somatic deletion of the KLF4 gene, using inducible and lineage-specific cre-transgenic mice, leads to a significant reduction of NK cells (NK1.1(+) TCR-β(-)) in the blood and spleen but not in the BM, liver, or LNs. Functional and immunophenotypic analyses revealed increased apoptosis of CD27(+/-) CD11b(+) NK cells in the spleen of KLF4-deficient mice, although remaining NK cells were able to lyse tumor target cells and produce IFN-γ. A normal recovery of adoptively transferred KLF4-deficient NK cells in WT hosts suggested that the survival defect was not intrinsic of NK cells. However, BM chimeras using KLF4-deficient mice as donors indicated that reduced survival of NK cells depended on BM-derived hematopoietic cells in the spleen. The number of CD11c(hi) DCs, which are known to support NK cell survival, was reduced significantly in the spleen of KLF4-deficient mice, likely a result of a lower number of precDC progenitor cells in this tissue. Taken together, our data suggest that the pluripotency-associated gene KLF4 is required for the maintenance of DCs in the spleen and consequently, survival of differentiated NK cells in this tissue.
自然杀伤 (NK) 细胞的发育和存活依赖于 NK 细胞中特定转录因子和造血细胞支持的组织特异性微环境所调控的复杂时空基因表达模式。在这里，我们利用诱导型和谱系特异性 cre 转基因小鼠对 KLF4 基因进行体细胞缺失，结果显示，NK 细胞（NK1.1(+)TCR-β(-)）在血液和脾脏中的数量显著减少，但在骨髓、肝脏或淋巴结中没有减少。功能和免疫表型分析显示，KLF4 缺失小鼠脾脏中 CD27(+/-)CD11b(+)NK 细胞的凋亡增加，尽管剩余的 NK 细胞仍能够裂解肿瘤靶细胞并产生 IFN-γ。在 WT 宿主中过继转移的 KLF4 缺失 NK 细胞的正常恢复表明，NK 细胞的存活缺陷不是内在的。然而，利用 KLF4 缺失小鼠作为供体的 BM 嵌合体表明，NK 细胞在脾脏中的存活减少依赖于 BM 来源的造血细胞。已知支持 NK 细胞存活的 CD11c(hi)DC 的数量在 KLF4 缺失小鼠的脾脏中显著减少，这可能是由于该组织中前 DC 祖细胞的数量减少所致。综上所述，我们的数据表明，多能相关基因 KLF4 是维持脾脏中 DC 以及 NK 细胞在该组织中存活所必需的。
