Research ArticleFibrosis

T follicular helper–like cells contribute to skin fibrosis

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Science Translational Medicine  07 Mar 2018:
Vol. 10, Issue 431, eaaf5307
DOI: 10.1126/scitranslmed.aaf5307

Scleroderma’s little helpers

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–based mouse model to elucidate the key players in this disease. They observed that a subset of T follicular helper–like cells expressing inducible costimulator (ICOS) correlated with disease scores. Blocking these cells with anti-ICOS or anti–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)–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.

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