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

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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.