?? T cells attenuate bleomycin-induced fibrosis through the production of CXCL10.
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ABSTRACT: ?? T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ?? T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ? chain of the ?? T-cell receptor (?? knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ?? KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ?? KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ?? T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ?? T cells produced substantial quantities of all four of these cytokines, suggesting that ?? T cells are a predominant source of these proteins. To demonstrate that ?? T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ?? T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ?? KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ?? KO mice. Finally, adoptive transfer of ?? T cells from CXCL10(-/-) mice failed to reverse the severe fibrosis in ?? KO mice. These results indicate that ?? T cells promote the resolution of fibrosis through the production of CXCL10.
SUBMITTER: Pociask DA
PROVIDER: S-EPMC3070585 | biostudies-literature | 2011 Mar
REPOSITORIES: biostudies-literature
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