The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus.
The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus.
复制标题
DOI：
10.18632/oncotarget.15241
复制
发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Crompton T
中科院分区：
文献类型：
--
作者：
Lau CI;Barbarulo A;Solanki A;Saldaña JI;Crompton T
Kif7是一种纤毛运动蛋白，通过影响初级纤毛的结构来调节哺乳动物Hedgehog通路的激活。在这里，我们展示了Kif7是正常T细胞发育所必需的，尽管T细胞缺乏初级纤毛。对Kif7缺陷胸腺的分析表明，Kif7缺陷增加了早期CD44+CD25+CD4-CD8-胸腺祖细胞的数量，但减少了向CD4+CD8+双阳性(DP)细胞的分化。在从DP向成熟T细胞的转变过程中，Kif7缺乏选择性地延迟了向CD8系的成熟。由于胸腺细胞固有的Kif7缺乏，与TCR信号强度相关的CD5在DP和成熟的CD4和CD8细胞上的表达减少，来自放射嵌合体的Kif7缺陷T细胞在体外被抗CD3和抗CD28刺激时激活效率降低。Kif7缺陷的胸腺细胞表现出比WT更高的Hedgehog靶基因ptch1的表达，但对重组Shh的处理不那么敏感，并且Kif7缺陷的T细胞的发育不能中和内源性HH蛋白，这表明Kif7缺陷的胸腺细胞无法解释Hedgehog信号的变化。此外，Kif7缺乏降低了胸腺上皮细胞表面MHCII的表达。
Kif7 is a ciliary kinesin motor protein that regulates mammalian Hedgehog pathway activation through influencing structure of the primary cilium. Here we show that Kif7 is required for normal T-cell development, despite the fact that T-cells lack primary cilia. Analysis of Kif7-deficient thymus showed that Kif7-deficiency increases the early CD44+CD25+CD4-CD8- thymocyte progenitor population but reduces differentiation to CD4+CD8+ double positive (DP) cell. At the transition from DP to mature T-cell, Kif7-deficiency selectively delayed maturation to the CD8 lineage. Expression of CD5, which correlates with TCR signal strength, was reduced on DP and mature CD4 and CD8 cells, as a result of thymocyte-intrinsic Kif7-deficiency, and Kif7-deficient T-cells from radiation chimeras activated less efficiently when stimulated with anti-CD3 and anti-CD28 in vitro. Kif7-deficient thymocytes showed higher expression of the Hedgehog target gene Ptch1 than WT, but were less sensitive to treatment with recombinant Shh, and Kif7-deficient T-cell development was refractory to neutralisation of endogenous Hh proteins, indicating that Kif7-deficient thymocytes were unable to interpret changes in the Hedgehog signal. In addition, Kif7-deficiency reduced cell-surface MHCII expression on thymic epithelial cells.