Abstract
BACKGROUND: Interstitial lung disease (ILD) is the most frequent complication of systemic sclerosis (SSc), associated with a poor prognosis and limited treatments. T helper 2 (Th2) cells play a key role in SSc pathogenesis, with T cell inducible co-stimulator (ICOS) involved in Th2 differentiation and IL-4 expression. However, the specific role of ICOS(+) Th2 cells in SSc-ILD remains unclear. METHODS: Peripheral blood mononuclear cells (PBMCs) from SSc patients and healthy controls were analyzed via mass cytometry (CyTOF). The CD4(+)CXCR5(−)ICOS(+)IL-4(+) T cell subset was further characterized using flow cytometry. In vitro, human lung fibroblasts were co-cultured with differentiated CD4(+)ICOS(+)IL-4(+) cells, and fibrotic gene expression was measured. An in vivo SSc-ILD model was induced via bleomycin instillation, and the frequency of CD4(+)CXCR5(−)ICOS(+)IL-4(+) cells was assessed in the lung. Functional contributions were evaluated by transferring CD4(+)ICOS(+)IL-4(+) cells into Rag2(−/−) mice, followed by histological analysis of lung inflammation and fibrosis. RESULTS: CyTOF identified a CD4(+)CCR4(+)ICOS(+) T cell subset significantly increased in SSc-ILD patients, defined as ICOS(+) Th2 cells by the absence of CXCR5, CXCR3, and CCR6 and the presence of CCR4. Elevated CD4(+)CXCR5(−)ICOS(+)IL-4(+) T cells were confirmed in SSc-ILD patient PBMCs and in the lungs of bleomycin-treated mice. Functionally, ICOS(+) Th2 cells induced high expression of Vimentin, Fibronectin, and α-SMA in fibroblasts when co-cultured with TGF-β. Adoptive transfer of ICOS(+) Th2 cells into Rag2(−/−) mice caused lung inflammation and upregulated fibrosis-related genes, including α-SMA, Col1a1, Col1a2, and Col3a1. CONCLUSION: This study identifies ICOS(+) Th2 cells as a key subset contributing to SSc-ILD inflammation and fibrosis, highlighting their potential as therapeutic targets. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-026-01455-y.