Mesenchymal stromal cells ameliorate systemic sclerosis-interstitial lung disease via PD-1/PD-L1 signalling axis.

OBJECTIVE: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by progressive pulmonary fibrosis. This study aimed to investigate the role of programmed death-1 (PD-1)-expressing T cells in SSc-ILD pathogenesis and evaluate the therapeutic potential and mechanism of mesenchymal stromal cells (MSCs) in mitigating fibrosis. METHODS: PD-1 expression in T cells from 30 patients with SSc (including SSc-ILD and SSc-non-ILD (nILD) subgroups) and 15 healthy controls (HCs) was analysed via flow cytometry. A bleomycin (BLM)-induced SSc-ILD mouse model was established to evaluate the effects of MSCs in the treatment of lung collagen deposition and inflammation in SSc-ILD. MSCs were administered intravenously to BLM-treated mice, with programmed death-ligand 1 (PD-L1) knockdown (using small interfering RNA targeting PD-L1, siPD-L1) used to explore the mechanism of MSCs on PD-1/PD-L1 pathway. The effects of MSCs on CD4(+)PD-1(+) T cell proliferation and apoptosis were evaluated by in vitro co-culture experiment. RESULTS: PD-1 expression was significantly elevated in CD3(+) and CD4(+) T cells of patients with SSc-ILD compared with HCs and SSc-nILD subgroups. In BLM-induced mice, CD4(+)PD-1(+) T cells in the lung tissues increased progressively, which was correlated with the severity of lung fibrosis. CD4(+)PD-1(+) T cells directly stimulated fibroblasts to upregulate the expression of collagen and transforming growth factor β1. Treatment with MSCs reduced pulmonary inflammation, fibrosis and PD-1(+) T cell frequencies in lung tissues of BLM-induced mice. This therapeutic effect was PD-L1-dependent, as it was mediated by the MSC-induced suppression. CONCLUSION: CD4(+)PD-1(+) T cells drive fibrosis in SSc-ILD, and MSCs ameliorate disease by suppressing PD-1(+) T cells through PD-L1-mediated mechanisms. These findings highlight PD-1 as a therapeutic target and support the clinical investigation of MSC-based interventions for SSc-ILD.