The transcription factor E4BP4 is not required for extramedullary pathways of NK cell development.
The transcription factor E4BP4 is not required for extramedullary pathways of NK cell development.
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DOI：
10.4049/jimmunol.1302765
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发表时间：
2014-03-15
期刊：
影响因子：
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通讯作者：
Wack A
中科院分区：
文献类型：
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作者：
Crotta S;Gkioka A;Male V;Duarte JH;Davidson S;Nisoli I;Brady HJ;Wack A
NK细胞有助于抗肿瘤和抗病毒免疫监视。它们在骨髓（BM）中的发育需要转录因子E4 BP 4/NFIL 3，但在其他器官中的需求不太明确。在这项研究中，我们发现在E4 BP 4缺陷小鼠的胸腺、脾脏和肝脏中发现了未成熟表型的CD 3 −NK1.1+ NKp 46 + CD 122 + NK细胞，表达低水平的中胚层，而成熟的、高水平的传统NK细胞数量急剧减少。E4 BP 4缺陷型CD 44 + CD 25 −双阴性1胸腺细胞在体外有效发育为NK细胞，其动力学、表型和功能与野生型对照相似，而E4 BP 4缺陷型BM前体细胞则不发育为NK细胞。在E4 BP 4/Rag-1双缺陷（DKO）小鼠中，在胸腺和肝脏中发现了类似于Rag-1缺陷对照中的NK细胞，数量相似。然而，NK前体在DKO BM中减少，并且在体外没有NK细胞从DKO BM祖细胞发育。DKO胸腺细胞前体容易发育成NK细胞，但DKO BM转移到裸受体中，E4 BP 4/Rag-1/IL-7三重KO小鼠中的NK细胞表明胸腺非依赖性NK细胞发育。在T细胞或E4 BP 4充足的NK细胞存在下，DKO NK细胞具有选择性劣势，并且当过继转移到淋巴细胞减少宿主中时，胸腺和肝脏DKO NK细胞显示出降低的存活率。这与体外较高的凋亡率和对IL-15较低的反应性相关。总之，我们证明了E4 BP 4独立的发展NK细胞的不成熟表型，健身减少，短t1/2，和潜在的髓外起源。我们的数据确定了E4 BP 4独立的NK细胞发育途径和E4 BP 4在NK细胞稳态中的作用。
NK cells contribute to antitumor and antiviral immunosurveillance. Their development in the bone marrow (BM) requires the transcription factor E4BP4/NFIL3, but requirements in other organs are less well defined. In this study, we show that CD3−NK1.1+NKp46+CD122+ NK cells of immature phenotype and expressing low eomesodermin levels are found in thymus, spleen, and liver of E4BP4-deficient mice, whereas numbers of mature, eomesoderminhigh conventional NK cells are drastically reduced. E4BP4-deficient CD44+CD25− double-negative 1 thymocytes efficiently develop in vitro into NK cells with kinetics, phenotype, and functionality similar to wild-type controls, whereas no NK cells develop from E4BP4-deficient BM precursors. In E4BP4/Rag-1 double-deficient (DKO) mice, NK cells resembling those in Rag-1–deficient controls are found in similar numbers in the thymus and liver. However, NK precursors are reduced in DKO BM, and no NK cells develop from DKO BM progenitors in vitro. DKO thymocyte precursors readily develop into NK cells, but DKO BM transfers into nude recipients and NK cells in E4BP4/Rag-1/IL-7 triple-KO mice indicated thymus-independent NK cell development. In the presence of T cells or E4BP4-sufficient NK cells, DKO NK cells have a selective disadvantage, and thymic and hepatic DKO NK cells show reduced survival when adoptively transferred into lymphopenic hosts. This correlates with higher apoptosis rates and lower responsiveness to IL-15 in vitro. In conclusion, we demonstrate E4BP4-independent development of NK cells of immature phenotype, reduced fitness, short t1/2, and potential extramedullary origin. Our data identify E4BP4-independent NK cell developmental pathways and a role for E4BP4 in NK cell homeostasis.