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

NZB（新西兰黑）和NZW（新西兰白色）小鼠品系的F1杂交小鼠作为系统性红斑狼疮（SLE）的小鼠模型进行了研究。在杂交小鼠中，B1（CD 5+）细胞被证明是负责自身抗体的产生。然而，这些小鼠的SLE表型的表达严格依赖于CD 4 + T细胞。这些小鼠表现出年龄依赖性的自发活化和外周CD 4 + T细胞的亚群偏斜，如异常细胞因子产生、早期活化标志物CD 69阳性的CD 4 + T细胞的频率升高和分化标志物CD 62 L和/或NTA 260阳性的CD 4 + T细胞的频率降低所反映的。为了研究（NZB x NZW）F1小鼠外周血CD 4 ^+ T细胞异常特征的遗传控制，我们对（NZB x .NZW）F1 x NZW回交小鼠脾脏中调节CD 69 + CD 4+、CD 62 L + CD 4+和NTA 260 + CD 4 + T细胞频率的数量性状位点（QTL）进行了全基因组定位。CD 69 + CD 4 + T细胞频率升高，CD 62 L + CD 4+和NTA 260 + CD 4 + T细胞频率降低，均受常见的多基因控制，其中MHC II类基因座杂合性和12号染色体上迄今未知的Sta-1（自发T细胞活化）基因座的相互作用起主要作用。这些遗传相互作用与B1细胞异常功能所涉及的遗传相互作用不同。因此，在（NZB x NZW）F1小鼠中，CD 4 + T细胞和B1细胞的功能异常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.