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A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice
Authors:Valerie A. Wallace  Seiji Kondo  Takeshi Kono  Zhou Xing  Emma Timms  Caren Furlonger  Edward Keystone  Jack Gauldie  Daniel N. Sauder  Tak W. Mak  Christopher J. Paige
Abstract:The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4−/− and CD8−/−) mice. Tsk/+ CD4−/− mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8−/− mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.
Keywords:Tight skin mouse  Skin fibrosis  Autoimmune disease  CD4+ T cells  CD8+ T cells
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