T follicular helper–like cells contribute to skin fibrosis

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 (T H ) and T follicular helper (T FH ) 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 T FH -like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS + T FH -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 + T FH -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 + T FH -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.