Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif
Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif
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DOI：
10.1093/intimm/dxh155
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Zerrahn, J
中科院分区：
文献类型：
--
作者：
Geserick, P;Kaiser, F;Zerrahn, J
调控造血细胞发育和分化的调控网络还不完全清楚。Schlafen（Slfn）蛋白家族的成员已经涉及细胞生长和T细胞发育的调节。我们已经确定和染色体定位四个新成员，slfn 5，slfn 8，slfn 9和slfn 10，这属于一个不同的亚组内的这个基因家族。这些蛋白质的特征是存在序列基序，将它们鉴定为DNA/RNA解旋酶超家族I的不同成员。这些新鉴定的成员在造血细胞分化中的重要作用是基于它们的差异调节而提出的：（i）在发育和活化的T细胞中，（ii）在LPS或IFN γ活化的巨噬细胞中，（iii）在IL 6或LIF驱动的成髓细胞M1细胞终末分化成巨噬细胞样细胞时，和（iv）在感染单核细胞增生李斯特菌的小鼠的脾细胞中。与野生型细胞相反，IRF-1和IFN α/β R缺陷型巨噬细胞虽然经历生长停滞，但在IFN γ或LPS刺激后分别不能上调slfn基因表达。因此，IFN γ或LPS诱导的生长停滞的基本参与似乎是不可能的。同样，新鉴定的slfn家族成员在成纤维细胞中的异位表达没有显示对生长控制的一般影响。与此相反，转基因T细胞特异性表达的一个代表性成员，这个新的亚家族，slfn 8，导致严重受损的T细胞发育和外周T细胞显示出降低的增殖潜力。因此，slfn 8在控制T细胞发育和生长的调控网络中的功能参与似乎是细胞类型特异性的。
The regulatory networks governing development and differentiation of hematopoietic cells are incompletely understood. Members of the Schlafen (Slfn) protein family have been implicated in the regulation of cell growth and T cell development. We have identified and chromosomally mapped four new members, slfn5, slfn8, slfn9 and slfn10, which belong to a distinct subgroup within this gene family. The characteristic feature of these proteins is the presence of sequence motifs identifying them as distinct members of the superfamily I of DNA/RNA helicases. A significant role of these newly identified members in hematopoietic cell differentiation is suggested based on their differential regulation (i) in developing and activated T cells, (ii) in LPS or IFNgamma activated macrophages, (iii) upon IL6 or LIF driven terminal differentiation of myeloblastic M1 cells into macrophage-like cells, and (iv) in splenocytes of mice infected with Listeria monocytogenes. In contrast to wild-type cells, IRF-1 and IFNalpha/betaR deficient macrophages, although undergoing growth arrest, fail to upregulate slfn gene expression upon IFNgamma or LPS stimulation, respectively. Therefore, an essential participation in IFNgamma or LPS induced growth arrest appears unlikely. Likewise, ectopic expression of the newly identified slfn family members in fibroblasts did not reveal a general impact on growth control. In contrast, transgenic T-cell specific expression of a representative member of this new subfamily, slfn8, resulted in profoundly impaired T cell development and peripheral T cells showed a reduced proliferative potential. Thus, functional participation of slfn8 in the regulatory networks governing T cell development and growth appears to be cell type specific.