A role for T helper 2 cells in mediating skin fibrosis in tight-skin mice.
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.
Ong
C J
CJ
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Ip
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Teh
S J
SJ
Wong
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Jirik
F R
FR
Grusby
M J
MJ
Teh
H S
HS
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000276:immunology / Q000473:pathology; D006183:H-2 Antigens / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D050800:STAT6 Transcription Factor; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology
D006183:H-2 Antigens; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C109168:T-cell receptor Vbeta 8.2; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma