@article {Tayloreaaf5307, author = {Taylor, Devon K. and Mittereder, Nanette and Kuta, Ellen and Delaney, Tracy and Burwell, Timothy and Dacosta, Karma and Zhao, Weiguang and Cheng, Lily I. and Brown, Charles and Boutrin, Anmarie and Guo, Xiang and White, Wendy I. and Zhu, Jie and Dong, Huifang and Bowen, Michael A. and Lin, Jia and Gao, Changshou and Yu, Li and Ramaswamy, Madhu and Gaudreau, Marie-Claude and Woods, Rob and Herbst, Ronald and Carlesso, Gianluca}, title = {T follicular helper{\textendash}like cells contribute to skin fibrosis}, volume = {10}, number = {431}, elocation-id = {eaaf5307}, year = {2018}, doi = {10.1126/scitranslmed.aaf5307}, publisher = {American Association for the Advancement of Science}, abstract = {Scleroderma, also known as systemic sclerosis, is a devastating disease involving multi-organ fibrosis. Taylor et al. examined immune cells from patients and in the skin of a graft-versus-host disease{\textendash}based mouse model to elucidate the key players in this disease. They observed that a subset of T follicular helper{\textendash}like cells expressing inducible costimulator (ICOS) correlated with disease scores. Blocking these cells with anti-ICOS or anti{\textendash}IL-21, an important T follicular helper cell cytokine, ameliorated disease in the mouse model. Targeting these not-so-helpful T cells could dampen dermal fibrosis and bring relief to scleroderma patients.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){\textendash}SSc mice and contributed to dermal fibrosis via an interleukin-21{\textendash} and matrix metalloproteinase 12{\textendash}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.}, issn = {1946-6234}, URL = {https://stm.sciencemag.org/content/10/431/eaaf5307}, eprint = {https://stm.sciencemag.org/content/10/431/eaaf5307.full.pdf}, journal = {Science Translational Medicine} }