Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis.

Systemic sclerosis (SSc or scleroderma) is an idiopathic disorder of connective tissue characterized by vascular abnormalities, immune cell activation and cutaneous and visceral fibrosis 1. Its most characteristic feature is cutaneous fibrosis attributable to excessive deposition of collagen and other connective tissue components by activated dermal fibroblasts 2. Although the pathogenesis is still unclear, this activation is believed to result from fibroblast interaction with immune mediators and other growth factors 2,3. Microscopic and immunohistochemical studies of skin biopsies from various clinical stages of SSc indicate that vascular injury and endothelial damage are the earliest observable events in pathogenesis 2,4–6, possibly initiated by viruses, autoantibodies, granzymes or oxidative products 2,7. Infiltration of activated lymphocytes and macrophages into the affected skin follows, preceding worsening of vasculopathy and fibrosis 4–6. Interestingly, in situ hybridization studies have demonstrated that collagen synthesizing fibroblasts are located in close proximity to small blood vessels and to the perivascular inflammatory infiltrate 8, thus supporting the hypothesis that inflammatory cells provide important stimuli that drive collagen synthesis in fibroblasts. Macrophages and T lymphocytes represent the predominant cell type of the inflammatory infiltrates in the dermis of SSc patients 4–6,9. Such infiltrating T cells exhibit increased expression of activation markers and show signs of antigen-driven expansion 10,11. While their antigen specificity is not known, T cell-derived cytokines have been implicated in the induction of fibrosis 12. We recently found that dysregulated production of the profibrotic cytokine IL-13 by peripheral blood effector CD8+ T cells is associated with more severe skin thickening in SSc 13 and defects in the molecular control of IL-13 production 14. Other studies have suggested that IL-13 plays a role in the pathogenesis of SSc 15–17, however direct evidence of the source and role of IL-13 in SSc patients is still unclear. IL-13 is an immunoregulatory cytokine predominantly secreted by activated Th2 cells, and is involved in the pathogenesis of many fibrotic diseases 18. Although most studies to date have focused on CD4+ T cells because of the strong MHC class II HLA associations in some SSc patient subsets and the presence of distinctive SSc autoantibodies 19, CD8+ T cells are also involved in the pathogenesis of SSc. Increased numbers of CD8+ T cells with elevated production of type 2 cytokines have been found in the bronchoalveolar lavage fluid of SSc patients with lung fibrosis 20, as well as increased numbers of IL-4-producing CD8+ T cells were found in the skin of SSc patients 21. Furthermore, our recent data have shown abnormalities in the number of circulating effector CD8+ T cells in patients with SSc as well as in their cytokine production ability compared to normal individuals 13,22. In the present study we provide new insight into the pathogenesis of skin fibrosis in SSc by showing that CD8+ T cells and IL-13+ cells are numerous in the skin lesions of patients, particularly in the early stages of the disease. Furthermore, we demonstrate that IL-13 produced by circulating skin-homing CD8+ T cells from SSc patients is able to induce a pro-fibrotic functional phenotype in normal skin fibroblasts. We conclude that IL-13 production by CD8+ T cells is directly involved in modulating dermal fibrosis in SSc and may represent an important target for future therapeutic intervention.