A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice

Mice heterozygous for the tight-skin (Tsh) mutation develop skin fibrosis. Previous studies have implicated a role for the immune system and, specific ally, CD4(+) T cells, in the etiology of skin fibrosis in Tsh/+ mice. We ha ve recently shown that the administration of neutralizing anti-IL-4 antibod ies 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 inve stigated the role of Th2 cells in mediating skin fibrosis in Tsk/+ mice. Pr evious studies have shown that the development of Th2 cells in non-Tsh mice is abrogated in mice with null mutation for either the IL-4 or the Stat6 g ene. In this study we showed that the polarization of CD4(+) T cells from T sh/+ mice toward the Th2 lineage is also dependent on a functioning IL-4 or State gene. More importantly, the development of skin fibrosis in Tsk/+ mi ce was abrogated by the IL4(-/-) or the Stat6(-/-) mutation. We also determ ined whether alteration of the TCR repertoire in Tsk/+ mice, achieved by th e introduction of TCR transgenes, was able to prevent the development of sk in fibrosis in Tsk/+ mice. We found that the exclusive usage of the V beta 8.2 gene segment by T cells was sufficient to prevent skin fibrosis in Tsh/ + mice. This result suggests that the exclusive use of this VP gene segment by T cells may have prevented the development of fibrosis-causing Th2 cell s. (C) 1999 Academic Press.