Lsh, an SNF2/helicase family member, is required for proliferation of mature T lymphocytes
Lsh, an SNF2/helicase family member, is required for proliferation of mature T lymphocytes
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DOI：
10.1073/pnas.97.9.4772
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发表时间：
2000-04-25
影响因子：
11.1
通讯作者：
Muegge, K
中科院分区：
文献类型：
--
作者：
Geiman, TM;Muegge, K
Lsh（Hells）与SNF 2/解旋酶家族成员密切相关，SNF 2/解旋酶家族成员重塑染色质，从而调节基因转录。在成年小鼠中，Lsh主要在淋巴组织中表达，在胸腺细胞中表达最高。Lsh基因在胸腺pro-T细胞中的表达可通过前T细胞受体交联诱导，在成熟T细胞中的表达可通过T细胞受体交联和CD_（28）共刺激诱导。为了探讨Lsh在淋巴发育或活化过程中的功能，我们在ES细胞中通过同源重组删除了Lsh基因。来自Lsh（-/-）的胎肝细胞被用作造血前体的来源以重建Rag 2（-/-）小鼠中的淋巴发育。Lsh-/-（与Lsh+/+或+/-相比）嵌合体显示胸腺细胞数量适度减少，这是由于T细胞发育从CD 4（-）CD 8（-）阶段向CD 4（+）CD 8（+）阶段过渡时的部分停滞。成熟的外周淋巴细胞数量减少至约60%的T细胞和40%的B细胞;然而，免疫受体基因的V（D）J重组是正常的。尽管Lsh-/- T细胞的多克隆活化诱导了正常水平的细胞因子，但细胞增殖受到严重抑制，细胞发生凋亡。除了Bcl-2实际上升高之外，参与凋亡调节的几个基因正常表达。这些结果表明，LSH不是强制性的正常淋巴发育，但外周T淋巴细胞的正常增殖是必不可少的。
Lsh (Hells) is closely related to SNF2/helicase family members that remodel chromatin and thus regulate gene transcription. In the adult mouse Lsh is expressed primarily in lymphoid tissue, showing the highest level in thymocytes, Lsh gene expression can be induced in thymic pro-T cells by pre-T cell receptor crosslinking and in mature T cells by T cell receptor crosslinking together with costimulation via CD28, The time course of Lsh gene and protein expression correlated closely with the onset of S phase of the cell cycle. To explore the function of Lsh during lymphoid development or activation, we deleted the Lsh gene by homologous recombination in ES cells. Fetal liver cells from Lsh(-/-) were used as a source of hematopoietic precursors to reconstitute lymphoid development in Rag2(-/-) mice. Lsh-/- (compared to Lsh+/+ or +/-) chimeras showed a modest reduction in thymocyte numbers due to a partial arrest at the transition from the CD4(-)CD8(-) stage to the CD4(+)CD8(+) stage of T cell development. Mature peripheral lymphocytes were reduced in number to approximate to 60% for T cells and 40% for B cells; however, V(D)J recombination of the immune receptor genes was normal. Although polyclonal activation of Lsh-/- T cells induced normal levels of cytokines, cell proliferation was severely suppressed and cells underwent apoptosis, Several genes involved in the regulation of apoptosis were expressed normally with the exception of Bcl-2 that was actually elevated. These findings demonstrate that Lsh is not obligatory for normal lymphoid development but is essential for normal proliferation of peripheral T lymphocytes.