Genetic control of the spontaneous activation of CD4+ Th cells in systemic lupus erythematosus (SLE)-prone (NZB x NZW) F1 mice

研究了新西兰黑（NZB）和新西兰白（NZW） F1杂交小鼠作为系统性红斑狼疮（SLE）小鼠模型。在杂交小鼠中，B1 （CD5+）细胞被证明负责自身抗体的产生。然而，这些小鼠SLE表型的表达严格依赖于CD4+ T细胞。这些小鼠表现出年龄依赖性的自发激活和外周CD4+ T细胞的亚群偏转，这反映在异常的细胞因子产生，CD4+ T细胞早期激活标记CD69阳性的频率升高，CD4+ T细胞分化标记CD62L和/或NTA260阳性的频率降低。为了研究（NZB x NZW） F1小鼠外周血CD4^+ T细胞异常特征的遗传调控，我们对（NZB x） F1小鼠脾脏中调节CD69+CD4+、CD62L+CD4+和NTA260+CD4+ T细胞频率的数量性状位点（QTL）进行了全基因组定位。NZW) F1 × NZW回交鼠。CD69+CD4+ T细胞频率升高，CD62L+CD4+和NTA260+CD4+ T细胞频率降低是在共同的多基因控制下，其中MHC II类位点的杂合性与12号染色体上一个迄今未知的位点sta1（自发T细胞激活）的相互作用起主要作用。这些遗传相互作用不同于B1细胞异常功能的相互作用。因此，在（NZB x NZW） F1小鼠中，CD4+ T细胞和B1细胞的异常功能是基于不同的多遗传易感性，这两者都有助于杂交小鼠SLE表型的表现。

The F1 hybrid of NZB (New Zealand Black) and NZW (New Zealand White) strains of mice has been studied as a murine model of systemic lupus erythematosus (SLE). In the hybrid mice, B1 (CD5+) cells were shown to be responsible for the autoantibody production. However, expression of SLE phenotypes of these mice is strictly dependent on CD4+ T cells. These mice show an age-dependent spontaneous activation and subset skewing of peripheral CD4+ T cells as reflected by the abnormal cytokine productions, elevated frequency of CD4+ T cells positive for an early activation marker CD69, and decreased frequencies of CD4+ T cells positive for the differentiation markers CD62L and/or NTA260. To study the genetic control of abnormal features of peripheral CD4^+ T cells in the ( NZB x NZW) F1 mice, we conducted genome-wide mapping of the quantitative trait loci (QTL) regulating the frequencies of CD69+CD4+, CD62L+CD4+ and NTA260+CD4+ T cells in the spleens of (NZB x .NZW) F1 x NZW backcross mice. Elevated frequency of CD69+CD4+ T cells, and decreased frequencies of CD62L+CD4+ and NTA260+CD4+ T cells were under the common multigenic control, in which interaction of the heterozygosity of the MHC class II loci and a hitherto unknown locus designated as Sta-1 ( spontaneous T-cell activation ) on chromosome 12 plays a major role. These genetic interactions were distinct from those involved in the abnormal functions of B1 cells. Therefore, in (NZB x NZW) F1 mice, abnormal functions of CD4+ T cells and B1 cells are based on distinct multi-genetic predisposition, both of which contribute to the manifestation of SLE phenotypes of the hybrid mice.