Lau Ching-In, Barbarulo Alessandro, Solanki Anisha, Saldaña José Ignacio, Crompton Tessa
Immunobiology Section, UCL Great Ormond Street Institute of Child Health, London, UK.
School of Health, Sport and Bioscience, University of East London, London, UK.
Oncotarget. 2017 Apr 11;8(15):24163-24176. doi: 10.18632/oncotarget.15241.
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.
Kif7是一种纤毛驱动蛋白，通过影响初级纤毛的结构来调节哺乳动物的Hedgehog信号通路激活。尽管T细胞缺乏初级纤毛，但我们发现Kif7是正常T细胞发育所必需的。对Kif7缺陷型胸腺的分析表明，Kif7缺陷会增加早期CD44+CD25+CD4-CD8-胸腺细胞祖细胞群体，但会减少向CD4+CD8+双阳性（DP）细胞的分化。在从DP细胞向成熟T细胞转变过程中，Kif7缺陷会选择性地延迟向CD8谱系的成熟。由于胸腺细胞内在的Kif7缺陷，DP细胞以及成熟的CD4和CD8细胞上与TCR信号强度相关的CD5表达降低，并且来自辐射嵌合体的Kif7缺陷型T细胞在体外受到抗CD3和抗CD28刺激时激活效率较低。Kif7缺陷型胸腺细胞显示出比野生型更高的Hedgehog靶基因Ptch1表达，但对重组Shh处理的敏感性较低，并且Kif7缺陷型T细胞发育对内源性Hh蛋白的中和具有抗性，这表明Kif7缺陷型胸腺细胞无法解读Hedgehog信号的变化。此外，Kif7缺陷会降低胸腺上皮细胞表面MHCII的表达。
