Wen Ben G, Pletcher Mathew T, Warashina Masaki, Choe Sun Hui, Ziaee Niusha, Wiltshire Tim, Sauer Karsten, Cooke Michael P
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5604-9. doi: 10.1073/pnas.0306907101. Epub 2004 Apr 2.
The mechanisms governing positive selection of T cells in the thymus are still incompletely understood. Here, we describe a N-ethyl-N-nitrosourea induced recessive mouse mutant, Ms. T-less, which lacks T cells in the peripheral blood because of a complete block of thymocyte development at the CD4(+)CD8(+) stage. Single nucleotide polymorphism mapping and candidate gene sequencing revealed a nonsense mutation in the inositol (1,4,5) trisphosphate 3 kinase B (Itpkb) gene in Ms. T-less mice. Accordingly, Ms. T-less thymocytes do not show detectable expression of Itpkb protein and have drastically reduced basal inositol (1,4,5) trisphosphate kinase activity. Itpkb converts inositol (1,4,5) trisphosphate to inositol (1,3,4,5) tetrakisphosphate, soluble second messengers that have been implicated in Ca(2+) signaling. Surprisingly, Ca(2+) responses show no significant differences between wild type (WT) and mutant thymocytes. However, extracellular signal-regulated kinase (Erk) activation in response to suboptimal antigen receptor stimulation is attenuated in Ms. T-less thymocytes, suggesting a role for Itpkb in linking T cell receptor signaling to efficient and sustained Erk activation.
胸腺中T细胞阳性选择的调控机制仍未完全明了。在此，我们描述了一种由N-乙基-N-亚硝基脲诱导产生的隐性小鼠突变体——无T细胞小鼠（Ms. T-less），该小鼠外周血中缺乏T细胞，因为其胸腺细胞发育在CD4(+)CD8(+)阶段完全受阻。单核苷酸多态性定位和候选基因测序显示，无T细胞小鼠的肌醇（1,4,5）三磷酸3激酶B（Itpkb）基因存在无义突变。相应地，无T细胞小鼠的胸腺细胞未检测到Itpkb蛋白表达，且基础肌醇（1,4,5）三磷酸激酶活性大幅降低。Itpkb可将肌醇（1,4,5）三磷酸转化为肌醇（1,3,4,5）四磷酸，这是参与Ca(2+)信号传导的可溶性第二信使。令人惊讶的是，野生型（WT）和突变型胸腺细胞之间的Ca(2+)反应没有显著差异。然而，在无T细胞小鼠的胸腺细胞中，针对次优抗原受体刺激的细胞外信号调节激酶（Erk）激活减弱，这表明Itpkb在将T细胞受体信号传导与高效且持续的Erk激活相联系中发挥作用。
