T follicular helper-like cells contribute to skin fibrosis
| Autor: | Jia Lin, Gianluca Carlesso, Nanette Mittereder, Xiang Guo, Huifang Dong, Wendy I. White, Li Yu, Michael A. Bowen, Karma Dacosta, Weiguang Zhao, Devon K. Taylor, Marie-Claude Gaudreau, Charles Brown, Ellen Kuta, Lily Cheng, Madhu Ramaswamy, Robert M. Woods, Tracy Delaney, Jie Zhu, Ronald Herbst, Changshou Gao, Anmarie Boutrin, Timothy Burwell |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Graft vs Host Disease Inflammation Matrix metalloproteinase Peripheral blood mononuclear cell Skin Diseases Scleroderma Inducible T-Cell Co-Stimulator Protein 03 medical and health sciences Mice 0302 clinical medicine Fibrosis medicine Animals Humans skin and connective tissue diseases Receptor Skin 030203 arthritis & rheumatology Mice Inbred BALB C Scleroderma Systemic integumentary system biology business.industry Interleukins General Medicine medicine.disease Pathophysiology 030104 developmental biology Immunology biology.protein Female Receptors Interleukin-21 medicine.symptom Antibody business |
| Zdroj: | Science translational medicine. 10(431) |
| ISSN: | 1946-6242 |
| Popis: | Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (TH) and T follicular helper (TFH) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS+ T cells and their contribution to inflammation and fibrosis in SSc are still unknown. We show that CD4+ ICOS-expressing T cells with a TFH-like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS+ TFH-like cells were found to be increased in the skin of graft-versus-host disease (GVHD)-SSc mice and contributed to dermal fibrosis via an interleukin-21- and matrix metalloproteinase 12-dependent mechanism. Administration of an anti-ICOS antibody to GVHD-SSc mice prevented the expansion of ICOS+ TFH-like cells and inhibited inflammation and dermal fibrosis. Interleukin-21 neutralization in GVHD-SSc mice blocked disease pathogenesis by reducing skin fibrosis. These results identify ICOS+ TFH-like profibrotic cells as key drivers of fibrosis in a GVHD-SSc model and suggest that inhibition of these cells could offer therapeutic benefit for SSc. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|