Y Chromosome-Linked B and NK Cell Deficiency in Mice
Y Chromosome-Linked B and NK Cell Deficiency in Mice
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DOI：
10.4049/jimmunol.1300303
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发表时间：
2013-06-15
影响因子：
4.4
通讯作者：
Ishii, Naoto
中科院分区：
文献类型：
--
作者：
Sun, Shu-lan;Horino, Satoshi;Ishii, Naoto
没有原发性免疫缺陷疾病与Y染色体有关，因为Y染色体不包含任何重要基因。我们已经建立了一种新的小鼠品系，其中所有雄性都缺乏B和NK细胞，并且具有派尔斑缺陷。到10周龄，100%的男性有明显的免疫缺陷。将这些免疫缺陷男性与两种不同遗传背景的野生型女性交配几代，证明免疫缺陷与Y染色体有关，并以孟德尔方式遗传。尽管荧光原位杂交分析显示，突变雄性小鼠的Y染色体比野生型雄性小鼠短三分之一，但外显子组测序并未发现任何显著的基因突变。精确的分子机制仍然未知。骨髓嵌合体分析表明，骨髓造血细胞的内在异常导致B和NK细胞缺陷。有趣的是，从突变雄性小鼠移植的胎肝细胞在淋巴细胞缺陷型IL 2 rg（-/-）受体小鼠中重建了B和NK细胞，而成年骨髓移植则没有。将B细胞发育的主要转录因子EBF基因导入突变的造血祖细胞，在体外和体内均挽救了B细胞而不是NK细胞的发育。这些Y染色体连锁免疫缺陷小鼠，具有优先的B和NK细胞缺陷，可能是一个有用的淋巴细胞发育模型。
There are no primary immunodeficiency diseases linked to the Y chromosome, because the Y chromosome does not contain any vital genes. We have established a novel mouse strain in which all males lack B and NK cells and have Peyer's patch defects. By 10 wk of age, 100% of the males had evident immunodeficiencies. Mating these immunodeficient males with wild-type females on two different genetic backgrounds for several generations demonstrated that the immunodeficiency is linked to the Y chromosome and is inherited in a Mendelian fashion. Although multicolor fluorescence in situ hybridization analysis showed that the Y chromosome in the mutant male mice was one third shorter than that in wild-type males, exome sequencing did not identify any significant gene mutations. The precise molecular mechanisms are still unknown. Bone marrow chimeric analyses demonstrated that an intrinsic abnormality in bone marrow hematopoietic cells causes the B and NK cell defects. Interestingly, fetal liver cells transplanted from the mutant male mice reconstituted B and NK cells in lymphocyte-deficient Il2rg(-/-) recipient mice, whereas adult bone marrow transplants did not. Transducing the EBF gene, a master transcription factor for B cell development, into mutant hematopoietic progenitor cells rescued B cell but not NK cell development both in vitro and in vivo. These Y chromosome-linked immunodeficient mice, which have preferential B and NK cell defects, may be a useful model of lymphocyte development.