Medical College of Wisconsin, Human and Molecular Genetics Center, Milwaukee, WI 53226, USA.
Genes Immun. 2013 Sep;14(6):380-6. doi: 10.1038/gene.2013.32. Epub 2013 May 30.
Reduced frequency of invariant natural killer T (iNKT) cells has been indicated as a contributing factor to type 1 diabetes (T1D) development in NOD mice. To further understand the genetic basis of the defect, we generated (NOD × ICR)F2 mice to map genes that control iNKT-cell development. We determined frequencies of thymic and splenic iNKT cells, as well as the ratio of CD4-positive and -negative subsets in the spleens of 209 F2 males. Quantitative trait loci (QTL) analysis revealed five loci that exceed the significant threshold for the frequency of thymic and/or splenic iNKT cells on Chromosomes (Chr) 1, 5, 6, 12 and 17. Three significant loci on Chr 1, 4 and 5 were found for the ratio of CD4-positive and -negative splenic iNKT cells. Comparisons with previously known mouse T1D susceptibility (Idd) loci revealed two significant QTL peak locations, respectively, mapped to Idd regions on Chr 4 and 6. The peak marker location of the significant Chr 12 iNKT QTL maps to within 0.5 Mb of a syntenic human T1D locus. Collectively, our results reveal several novel loci controlling iNKT-cell development and provide additional information for future T1D genetic studies.
在 NOD 小鼠中，固有自然杀伤 T(iNKT)细胞频率降低被认为是 1 型糖尿病(T1D)发展的一个促成因素。为了进一步了解该缺陷的遗传基础，我们生成了 (NOD×ICR)F2 小鼠，以绘制控制 iNKT 细胞发育的基因图谱。我们测定了 209 只雄性 F2 小鼠的胸腺和脾脏 iNKT 细胞频率，以及脾脏中 CD4 阳性和阴性亚群的比例。数量性状基因座(QTL)分析显示，在第 1、5、6、12 和 17 号染色体上，有 5 个位点的胸腺和/或脾脏 iNKT 细胞频率超过显著阈值。在第 1、4 和 5 号染色体上发现了 3 个与 CD4 阳性和阴性脾脏 iNKT 细胞比例相关的显著位点。与先前已知的小鼠 T1D 易感性(Idd)基因座的比较显示，两个显著的 QTL 峰位置分别映射到第 4 和 6 号染色体上的 Idd 区域。显著的第 12 号染色体 iNKT QTL 的峰值标记位置位于与人类 T1D 基因座 0.5Mb 以内的同源区域。总的来说，我们的结果揭示了几个控制 iNKT 细胞发育的新基因座，并为未来的 T1D 遗传研究提供了更多信息。
