Ong C J, Ip S, Teh S J, Wong C, Jirik F R, Grusby M J, Teh H S
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Cell Immunol. 1999 Aug 25;196(1):60-8. doi: 10.1006/cimm.1999.1537.
Mice heterozygous for the tight-skin (Tsk) mutation develop skin fibrosis. Previous studies have implicated a role for the immune system and, specifically, CD4(+) T cells, in the etiology of skin fibrosis in Tsk/+ mice. We have recently shown that the administration of neutralizing anti-IL-4 antibodies to Tsk/+ mice prevented the development of skin fibrosis in these mice. Since IL-4 is a major cytokine produced by T helper 2 (Th2) cells, we investigated the role of Th2 cells in mediating skin fibrosis in Tsk/+ mice. Previous studies have shown that the development of Th2 cells in non-Tsk mice is abrogated in mice with null mutation for either the IL-4 or the Stat6 gene. In this study we showed that the polarization of CD4(+) T cells from Tsk/+ mice toward the Th2 lineage is also dependent on a functioning IL-4 or Stat6 gene. More importantly, the development of skin fibrosis in Tsk/+ mice was abrogated by the IL4(-/-) or the Stat6(-/-) mutation. We also determined whether alteration of the TCR repertoire in Tsk/+ mice, achieved by the introduction of TCR transgenes, was able to prevent the development of skin fibrosis in Tsk/+ mice. We found that the exclusive usage of the Vbeta8.2 gene segment by T cells was sufficient to prevent skin fibrosis in Tsk/+ mice. This result suggests that the exclusive use of this Vbeta gene segment by T cells may have prevented the development of fibrosis-causing Th2 cells.
携带紧皮（Tsk）突变的杂合子小鼠会发生皮肤纤维化。先前的研究表明，免疫系统尤其是CD4(+) T细胞在Tsk/+小鼠皮肤纤维化的病因中起作用。我们最近发现，给Tsk/+小鼠注射中和性抗IL-4抗体可阻止这些小鼠发生皮肤纤维化。由于IL-4是辅助性T细胞2（Th2）产生的主要细胞因子，我们研究了Th2细胞在介导Tsk/+小鼠皮肤纤维化中的作用。先前的研究表明，在IL-4或Stat6基因发生无效突变的小鼠中，非Tsk小鼠中Th2细胞的发育被消除。在本研究中，我们表明来自Tsk/+小鼠的CD4(+) T细胞向Th2谱系的极化也依赖于功能正常的IL-4或Stat6基因。更重要的是，IL4(-/-)或Stat6(-/-)突变消除了Tsk/+小鼠皮肤纤维化的发展。我们还确定，通过引入TCR转基因实现的Tsk/+小鼠TCR库的改变是否能够阻止Tsk/+小鼠皮肤纤维化的发展。我们发现T细胞对Vbeta8.2基因片段的排他性使用足以阻止Tsk/+小鼠发生皮肤纤维化。这一结果表明，T细胞对该Vbeta基因片段的排他性使用可能阻止了导致纤维化的Th2细胞的发育。
