Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis

Takashi Maehara, Naoki Kaneko, Cory A. Perugino, Hamid Mattoo, Jesper Kers, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Samuel J.H. Murphy, Musie Ghebremichael, David Fox, Aimee S. Payne, Robert Lafyatis, John H. Stone, Dinesh Khanna, Shiv Pillai

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Abstract

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

Original languageEnglish
Pages (from-to)2451-2464
Number of pages14
JournalJournal of Clinical Investigation
Volume130
Issue number5
DOIs
Publication statusPublished - May 1 2020

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Maehara, T., Kaneko, N., Perugino, C. A., Mattoo, H., Kers, J., Allard-Chamard, H., Mahajan, V. S., Liu, H., Murphy, S. J. H., Ghebremichael, M., Fox, D., Payne, A. S., Lafyatis, R., Stone, J. H., Khanna, D., & Pillai, S. (2020). Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. Journal of Clinical Investigation, 130(5), 2451-2464. https://doi.org/10.1172/JCI131700