Interleukin-13–producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis
Corresponding Author
Patrizia Fuschiotti
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST W1052, Pittsburgh, PA 15261Search for more papers by this authorAdriana T. Larregina
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorJohnan Ho
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorCarol Feghali-Bostwick
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorThomas A. Medsger Jr.
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorCorresponding Author
Patrizia Fuschiotti
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST W1052, Pittsburgh, PA 15261Search for more papers by this authorAdriana T. Larregina
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorJohnan Ho
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorCarol Feghali-Bostwick
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorThomas A. Medsger Jr.
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Search for more papers by this authorAbstract
Objective
Fibrosis is a major contributor to morbidity and mortality in systemic sclerosis (SSc). T cells are the predominant inflammatory infiltrate in affected tissue and are thought to produce cytokines that drive the synthesis of extracellular matrix (ECM) proteins by fibroblasts, resulting in excessive fibrosis. We have previously shown that aberrant interleukin-13 (IL-13) production by peripheral blood effector CD8+ T cells from SSc patients correlates with the extent of skin fibrosis. The present study was undertaken to investigate the role of IL-13 production by CD8+ T cells in dermal fibrosis, an early and specific manifestation of SSc.
Methods
ECM protein production by normal dermal fibroblasts cocultured with SSc CD8+ T cell supernatants was determined by quantitative polymerase chain reaction and Western blotting. Skin-homing receptor expression and IL-13 production by CD8+ T cells in the peripheral blood of SSc patients were measured by flow cytometry. IL-13+ and CD8+ cells in sclerotic skin were identified by immunohistochemistry.
Results
IL-13–producing circulating CD8+ T cells from patients with SSc expressed skin-homing receptors and induced a profibrotic phenotype in normal dermal fibroblasts, which was inhibited by an anti–IL-13 antibody. High numbers of CD8+ T cells and IL-13+ cells were found in the skin lesions of SSc patients, particularly during the early inflammatory phase of the disease.
Conclusion
These findings show that IL-13–producing CD8+ T cells are directly involved in modulating dermal fibrosis in SSc. The demonstration that CD8+ T cells homing to the skin early in the course of SSc are associated with accumulation of IL-13 is an important mechanistic contribution to the understanding of the pathogenesis of dermal fibrosis in SSc and may represent a potential target for therapeutic intervention.
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